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Review

A Review of Repurposed Cancer Drugs in Clinical Trials for Potential Treatment of COVID-19

1
OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal
2
Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
*
Author to whom correspondence should be addressed.
Pharmaceutics 2021, 13(6), 815; https://doi.org/10.3390/pharmaceutics13060815
Submission received: 28 April 2021 / Revised: 26 May 2021 / Accepted: 28 May 2021 / Published: 30 May 2021
(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))

Abstract

:
The pandemic of the coronavirus disease 2019 (COVID-19) represents an unprecedented challenge to identify effective drugs for prevention and treatment. While the world’s attention is focused on news of COVID-19 vaccine updates, clinical management still requires improvement. Due to the similarity of cancer-induced inflammation, immune dysfunction, and coagulopathy to COVID-19, anticancer drugs, such as Interferon, Pembrolizumab or Bicalutamide, are already being tested in clinical trials for repurposing, alone or in combination. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected, clinicians need effective medical treatments for this infection.

1. Introduction

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has caused catastrophic damage to human life. Since December 2019, the pandemic has spread worldwide and still is ongoing. SARS-CoV-2 primarily infects the upper and lower respiratory tract; however, it can also affect other vital organs. Most people recover from the acute phase of the disease, but some people continue to experience a range of effects for months after recovery. Clinical management is currently focused on supportive care and prevention and control of complications such as acute respiratory distress syndrome (ARDS) [1].
Although the world’s attention is understandably centred on reports of COVID-19 vaccine updates, from supply to administration, the need for treatments cannot be overlooked, as vaccination cannot protect everybody and as infection overwhelms hospitals and nursing homes. When we compare COVID-19 to the common flu, which is routinely targeted and has readily available and effective vaccines, we can see that no vaccine is ideal. Therefore, flu medications are still in high demand to avoid hospitalization and save lives. While the rise of new variants of COVID-19 threatens the efficacy of the available vaccines, it is critical that we must continue researching therapies to minimize hospitalization and cure COVID-19. The world health organization created (WHO) guidelines on using vaccines and antivirals during influenza pandemics to address the shortage of vaccines and antivirals [2]. Demonstrating that with therapy, people can live longer and gain control over the pandemic’s curse, as the likelihood of people becoming ill and spreading the disease decreases. Therapeutics also can be used as prophylactics to prevent hospitalizations and severe cases of the disease.
The food and drug administration (FDA) granted emergency use authorization to two monoclonal antibody treatments for non-hospitalized adults and children over the age of 12 who have mild to moderate COVID-19 symptoms, who are at risk for developing severe COVID-19 or being hospitalized for it. Regeneron’s casirivimab and imdevimab combo and Eli Lilly’s bamlanivimab and etesevimab combination are the two treatmentsPrior approval for the single use of bamlanivmab to treat COVID-19 was withdrawn in April 2021 due to new data revealing minimal efficacy [3]. While these medications can be beneficial, the need for intravenous administration (IV) requires a visit to a clinic or hospital immediately after symptoms appear, which limits their use.
Consequently, effective therapies, which are available to anyone who needs them, must work with various populations and ensure that the responses to the pandemic are globally successful and inclusive. Having both important tools in our arsenal would ensure that most of the population is shielded from the severe effects of COVID-19. However, the development of novel antiviral drugs needs long-term investigation in clinical trials. Therefore, the benefit of repurposing drugs to justify off-label usage is linked to the established safety profile. However, it may vary depending on the disease and the consolidated data on pharmacodynamics, pharmacokinetics and efficacy in phase I–IV trials [4,5]. Some host cell targets that interfere with the viral growth cycle, such as kinases, are commonly shared in the mechanisms of multiple viral infections and other conditions such as cancer, indicating the possibility of translating information through medical disciplines and disease models [6].
Several anticancer compounds were investigated as possible future drugs for COVID-19, among the thousands of coronavirus drugs studied. This article includes anticancer drugs that have already been approved or are being fast-tracked by regulatory authorities, supported by published evidence and used to treat the treatment of cancer patients. In times of crisis, such as COVID-19, drug repurposing is a valuable technique because it provides quick access to agents with not only accessible safety data but also defined manufacturing lines and supply chains, which facilitates the process of discovery. The major limitation of the use of repurposed therapeutics is associated with dosage regimens. Most of the time, effective concentrations needed for antiviral activity are often higher than those clinically attainable under the approved regimens [7].
Drug repurposing is not a reason for designing low-quality clinical trials or emphasizing the bias of early outcomes and uncontrolled cohorts, and it is desirable to use molecules with a specified safety profile. In addition, these therapies have early-and late-phase data on toxicity and complications management, which are especially helpful in the setting of a pandemic versus novel therapies. Several antineoplastic agents have the potential to improve COVID-19 outcomes by using the exact mechanisms and targets used in cancer treatment [8]. These targets are primarily associated with inhibiting cell division, regulating inflammation, and modulating the host-tumor microenvironment.

2. Materials and Methods

Using the OpenData Portal [9] was possible to research COVID-19-related drug repurposing data and experiments for all approved drugs. From this portal were only selected the anticancer drugs tested. Then was searched on the database of clinicaltrials.gov [10], the list of anticancer drugs tested on COVID-19 to see which were listed in clinical trials (20 May 2021). Additionally, searching through the site of European Pharmaceutical Review [11], in the news section, we were able to find more information about repurposed drugs and clinical trials for COVID-19. In the end, it was possible to formulate an updated list of anticancer drug candidates for COVID-19 treatment.

3. Viral, Host and Immune Targets in COVID-19

Antiviral therapy and prevention approaches are focused on (a) inhibiting the replication of the viral genome by either preventing the virus from entering the host cells or suppressing one or more phases of replication; (b) boosting the immune system and producing a type of antiviral memory via vaccination; (c) injection of antiviral antibodies generated in the plasma [12].
SARS-CoV-2 replicates similarly to other Coronaviridae viruses. Coronaviruses can infect the host through both endosomal and non-endosomal (cell surface) routes. The viral protein kinases and their associated signaling cascades have now been targeted in order to reduce coronavirus replication, particularly SARS-CoV-2. The virus can enter the cells via endocytosis or plasma membrane fusion through the interaction between the Spike (S) protein of the virus and angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) at the target cell [12,13].
After receptor-mediated endocytosis of the virus into the host cells, the virus releases the viral genome (single-stranded positive RNA) and uses the host ribosome to translate into viral polyproteins. Viral proteinases 3CLpro and PLpro cleave viral polyproteins into effector proteins (see Appendix A). RNA-dependent RNA polymerase, in turn, synthesizes a full-length negative-strand RNA template, which is used to make more viral genomic RNA. The viral genome then is synthesized by genomic replication, and four essential structural viral proteins (nucleocapsid (N), spike (S), membrane (M) and envelope (E)) are produced by transcription and translation [14]. The N protein binds genomic RNA, while S, M and E proteins are integrated into the membrane of the endoplasmic reticulum (ER), forming ERGIC—endoplasmic reticulum-Golgi intermediate compartment (also referred to as a vesicular-tubular cluster). The assembled nucleocapsid with helical twisted RNA is encapsulated into the ER lumen, viral progeny is transported by the ERGIC toward the plasma membrane of the host cell, and finally, the daughter virus is released by exocytosis [15].
The SARS-CoV-2 infection activates both innate and adaptive immune responses in the host. Patients with severe COVID-19 have a lower number of natural killer (NK) cells and a higher level of the C-reactive protein. The early failure of antiviral immunity during SARS-CoV-2 infection is correlated with a significant decrease in total T cells and NK cells [16].
Exploring potential clinical targets for COVID-19 attenuation is critical for long-term COVID-19 treatment.

4. Similarities of Cancer Immune Response and COVID-19

Cancer treatment is still a major challenge, but tremendous progress in anticancer drug discovery and development has occurred in the last few decades. The spent decades developing drugs for cancer-induced inflammation, immune dysfunction, and vascularization provided us with a number of drug options that could be useful in the treatment of other diseases.
Patients affected by COVID-19 also display inflammation, immune dysfunction and vascular syndrome dysfunction [17].
Evidence suggests that the immune response to SARS-CoV-2 can play different roles: dysregulated immune responses in critically ill patients with COVID-19 is reflected by lymphopenia, mainly affecting CD4+ T cells, including effector, memory, and regulatory T cells, and decreased IFN-γ expression in CD4+ T cells. Exhaustion of cytotoxic T lymphocytes, activation of macrophages, and a low human leukocyte antigen-DR expression on CD14 monocytes has been noted in patients with COVID-19 [18]. These similarities led scientists to consider anticancer therapy for the management of COVID-19 [8].
Furthermore, the homeostasis maintained by the vascular endothelium in health is affected by COVID-19 infection. In clinical studies, patients with COVID-19 have higher levels of fibrinogen, fibrin degradation products, and D-dimer, which appear to be related to disease severity and thrombotic risk [17]. Since the susceptibility to thrombotic events tends to be, at least in part, linked to inflammation and activation of the innate immune system that can cause systemic coagulation pathways. Therefore, the counterparts between the mechanisms of immunotherapy-related toxicities and the COVID-19 cytokine storm must be well considered in order not to affect the efficiency of the reused drug and increase the risk of the disease.

5. Repurposing Anticancer Drugs against COVID-19

The drug repurposing approach puts the drug discovery process on a fast track. COVID-19 researchers’ attention to its potential growth is wider in a range of different scientific fields. Due to the availability of in-vitro and in-vivo screening data, chemical optimization, toxicity studies, bulk manufacturing, formulation development and pharmacokinetic profiles of FDA-approved drugs, drug development cycles are shortened as all these critical steps can be bypassed [7,8]. In addition, there is no need for larger investments and repurposed drugs are proven to be safe in preclinical models, thus lowering the attrition rates as well. The main advantage of drug repurposing is associated with the established safety of the known candidate compounds. The development time frame and costs are substantially reduced when advancing a candidate into a clinical trial, which is possible without neglecting the comorbidities already associated with certain medications not to aggravate the patient condition provoked by the viral infection [6].
Several drugs that have been approved for cancer indication by the US FDA are now in COVID-19 clinical trials to test their efficiency in reducing mortality and speed up recovery. The following Table 1, Table 2, Table 3, Table 4, Table 5 and Table 6 represent anticancer drugs in clinical trials for COVID-19. In this review, we explore according to different categories of therapies which drugs represent more or fewer advantages for COVID-19. Appendix A is an updated list of all the anticancer drugs we could find or drugs used for the best supportive cancer care, which are being tested on their effectiveness to treat patients with mild to severe SARS-CoV-2.

5.1. Interferon-Based Therapies

The homeostasis maintained by the vascular endothelium in health is affected by COVID-19 infection. In clinical studies, patients with COVID-19 have higher levels of fibrinogen, fibrin degradation products, and D-dimer, which appear to be related to disease severity and thrombotic risk [19].
SARS-CoV-2 compromises the type 1 interferon antiviral response; therefore, IFN administration seemed a promising approach to stimulate macrophages, which engulf antigens and natural killer cells (NK cells). IFN might be able to strengthen the immune system by activating dormant components [20]. Clinical trials are running to test its effectiveness either alone or in combination with other drugs.
Ribavirin, lopinavir/ritonavir, remdesivir or hydroxychloroquine are some of the drugs tested in combination with IFNs in clinical trials (see Table 1). The study by Hung IF-N et al. demonstrated that early treatment with interferon beta-1b, lopinavir–ritonavir, and ribavirin is safe and highly effective in shortening the duration of the virus shedding, decreasing cytokine responses and allowing patients with mild to moderate disease to be discharged COVID-19 [21].
The problem is that when interferons boost the immune system, COVID-19 are likely to worsen before they improve. Giving anyone an interferon-based drug if they are still on a ventilator and their symptoms are about to overtake them may be fatal. This is why, in the case of viral infections, interferon therapies are usually only used as a last resort [22]. Nonetheless, interferon has already shown success against the antiviral activity, due to their ability to modulate the immune response, which is considered a “standard of care” in suppressing Hepatitis C and B infections [20].

5.2. Anticytokine Agents

The current COVID-19 infection is linked to elevated cytokine levels or hypercytokinemia. Patients who develop cytokine storms quickly experience cardiovascular collapse, multiple organ dysfunction and death [23]. The marked elevation of serum cytokines, especially tumor necrosis factor-alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6), is seen in patients with COVID-19 who go through pneumonia and hypoxia [24] (Table 2).
The administration of IL-6 blocking agents, such as tocilizumab and siltuximab, has been shown to be effective [25]. Repurposing tocilizumab would be interesting for the prevention or treatment of lung injury caused by COVID-19 since there is currently no effective antiviral therapy. In prospective studies, tocilizumab was linked to a lower relative risk of mortality, but the effects on other outcomes were inconclusive.
The drug siltuximab is a chimeric monoclonal antibody that binds to interleukin-6 (IL-6), preventing binding to soluble and membrane-bound interleukin-6 receptors. Current evidence showed that siltuximab led to a reduced mortality rate from COVID-19 promising to be a possible therapy; however, more studies are necessary [25].

5.3. Immune-Checkpoint Inhibitors

Immune checkpoints are regulatory molecules that are found on the surface of immune cells. When proteins on the surface of immune cells called T cells recognize and bind to partner proteins on other cells, such as tumor cells, immune checkpoints are activated. The T cells receive an “off” signal which may prevent cancer from being destroyed by the immune system. Therefore, immune checkpoint inhibitors are immunotherapy drugs that work by preventing checkpoint proteins from binding to their partner proteins. As a result, the “off” signal is not sent, allowing T cells to kill cancer cells [26,27].
The same principle can be applied for COVID-19 as a potential therapeutic approach (see Table 3). Evidence from preclinical models suggests that blocking programmed death receptor 1 (PD1) protects against RNA virus infections. Among the ICIs, antibodies capable of blocking the pathway of programmed death 1 (PD 1)/PD ligand-1 (PD L1) are promising. PD-1 expression levels on NK cells and T-cells were found to be highly upregulated in COVID-19 patients. When treated with anti-PD 1 and anti-PD L1 antibodies, they regain their T cell competence and effectively counteract viral infection [26,28]. Nivolumab and Pembrolizumab are ICIs that were successfully introduced into the management of various solid cancers, particularly for melanoma [24]. Currently, there is a phase II to trial to access efficacy for COVID-19. Pembrolizumab was tested in combination with tocilizumab [26].

5.4. Hormone Therapy

Androgen deprivation therapy (ADT), also known as androgen suppression therapy, is an antihormone therapy used to treat prostate cancer. Increasing evidence suggests that androgen has the potential to regulate the cellular TMPRSS2 expression and ACE2 [29].
TMPRSS2 is a membrane protease necessary for COVID pathogenesis, which is regulated by androgens. Blocking TMPRSS2 with bicalutamide can reduce viral replication and improve clinical outcomes. These agents may down-regulate TMPRSS2 mRNA and expression resulting in less entry of SARS-CoV-2 entry into cells and thus could arise as promising therapeutic tools in early SARS-CoV-2 infection and COVID-19 [30], see Table 4. A combination of bicalutamide in combination with camostat has the potential to reduce hospitalizations.
Toremifene used in the treatment of advanced breast cancer in postmenopausal women is a first-generation nonsteroidal-selective estrogen receptor modulator. It displays potential effects in blocking various viral infections, including MERS-CoV, SARS-CoV and Ebola virus. Prevents fusion between the viral and endosomal membrane by interacting with and destabilizing the virus membrane glycoprotein and eventually inhibiting viral replication [31]. Moreover, a preliminary study reveals a high potential for the synergistic effects of melatonin and toremifene to reduce viral infection and replication [32].

5.5. Inhibitor of Elongation Factor 1A and the Eukaryotic Initiation Factor 4A

Other molecules revealed potent pre-clinical efficacy against SARS-CoV-2 by inhibiting replication. In the life cycle of SARS-CoV-2, many host proteins play a role, and some are required for viral replication and translation. Drugs that target viral proteins are usually the focus of research, but a complementary approach is to target the required host proteins (Table 5).
Plitidepsin is an inhibitor of elongation factor 1A (eEF1A) and is an authorized drug in Australia for the treatment of multiple myeloma. Antiviral activity of plitidepsin has been analyzed in a human hepatoma cell line infected with the HCoV-229E-GFP virus, a virus similar to the SARS-CoV-2 virus [33]. Clinical studies using this drug are already taking place to assess safety and toxicity profile in patients with COVID-19 who require hospital admission, being the main goal is to select the recommended dose levels of plitidepsin for future phase 2/3 efficacy studies.
Another promising drug being tested in clinical trials is Zotatifin to assess its safety and tolerability. Zotatifin is a selective small-molecule inhibiting the eukaryotic initiation factor 4A (eIF4A), a powerful anti-proliferative target found at the intersection of the RAS and PI3K signaling pathways [34].

5.6. Blockade of Kinase Cascades

To test the hypothesis that PI3K blockade could hamper immune system hyperactivation and thus reduce lung inflammation and interfere with the viral cycle, researchers used one of the most successful targeted strategies in cancer treatment: kinase cascade blockade [35]. In a randomized placebo-controlled phase 2 study, Duvelisib, an orally bioavailable phosphatidylinositol 3-kinase (PI3K) selective inhibitor, is being evaluated for its ability to reduce inflammation in the lungs of patients with severe acute respiratory syndrome coronavirus 2 infections. As has been demonstrated repeatedly for multiple compounds in this pharmacological class, PI3K inhibitors, including the drug duvelisib, can cause lung inflammation and increase the risk of infections, and special caution is required during clinical trials using this class of molecules (Table 6).
On the other hand, Zanubrutinib is an irreversible Bruton tyrosine kinase inhibitor. The aberrant activation of the Bruton tyrosine kinase has a key role in the tumorigenesis of B-cell lymphoma. For COVID-19 evidence suggesting protective effects, a phase II trial is ongoing, aiming to reduce the disease-related immune dysregulation and hyper-inflammation [35].

5.7. Radiation and Prophylactic Vitamin D

Low-dose thoracic irradiation strategies with anti-inflammatory or prophylactic vitamin D have shown antiviral potential. However, there is a lack of direct pre-clinical and clinical evidence for COVID-19 and other therapeutics that may be more accessible, less risky, and less complicated for treatment [36].
Recently, we have acquired an unparalleled knowledge of the molecular processes and immune tolerance mechanisms regulating the occurrence and severity of human neoplasms, contributing to a wide variety of targeted anticancer and immunotherapy treatments [37]. Despite their specificity, however, small-molecule inhibitors and antibody-based therapies cause both on-and off-target effects, including immune-related pneumonia and diabetes, among other conditions, which need to be addressed when translating COVID-19 anticancer therapy. Now it is necessary to continue with clinical trials to overcome the uncertainties about the risks of certain therapeutics and understand which could be more beneficial in a time where vaccines are already available. Therapeutics along with immunization are the key to getting rid of the pandemic.

6. Conclusions

The COVID-19 pandemic has swiftly swept through the world, resulting in huge morbidity and significant mortality. While the news of vaccination brings the promise to the end of the pandemic, the importance of medicines must not be forgotten since it helps to limit the spread of disease and allows both prevention and treatment. Either using repurposed drugs, alone or in combination or even new molecules, the pandemic provides an opportunity to create new models for evaluating novel therapeutic approaches quickly. Due to similarities between cancer and COVID-19, anticancer drugs are repurposed in clinical trials to test their efficacy in targeting inflammation, immune dysfunction, and coagulopathy. Figure 1 illustrates the principal targets of anticancer drugs repurposed in clinical trials for COVID-19.
Finally, the management of the SARS-CoV-2 pandemic includes multidisciplinary collaboration to identify suitable treatment options for everyone, including and especially countries with limited access to vaccines and people already hospitalized. From the evidence reviewed here, several anticancer drugs seem to retain a promising activity to treat patients with COVID-19.

Author Contributions

B.C. contributed to the conception of the review; the collection, analysis and interpretation of the information included within; the drafting of the review; and critically revising the review for important intellectual content. N.V. contributed to the conception of the review; the collection, analysis and interpretation of the information included within; the drafting of the review; and critically revising the review for important intellectual content; Supervision, N.V.; project administration, N.V.; funding acquisition, N.V. Both authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by “Fundação para a Ciência e Tecnologia” (FCT, Portugal and FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, in the framework of the project IF/00092/2014/CP1255/CT0004.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

N.V. thanks Fundação para a Ciência e a Tecnologia (FCT, Portugal) for supporting these studies through a project from the National Funds, within CINTESIS, R&D Unit (reference UIDB/4255/2020). The contents of this report are solely the responsibility of the authors and do not necessarily represent the official view of the FCT.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

Coronavirus disease 2019 (COVID-19); severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); acute respiratory distress syndrome (ARDS); world health organization (WHO); the food and drug administration (FDA); interferons (IFNs); transmembrane-serine-protease-2 (TMPRSS2); angiotensin-converting enzyme 2 (ACE2); phosphatidylinositol 3-kinase (PI3K);elongation factor 1A (eEF1A); eukaryotic initiation factor 4A; the eukaryotic initiation factor 4A (eIF4A);programmed death receptor 1 (PD1); programmed death ligand-1 (PD L1); immune-checkpoint inhibitors (ICIs); tumor necrosis factor alpha (TNF-α);interleukin 17 (IL-17); interleukin 8 (IL-8);interleukin 6 (IL-6); Janus kinase (Jak); tyrosine kinases (Tyk); nucleocapsid (N); spike (S); membrane (M); envelope (E); endoplasmic reticulum (ER); endoplasmic reticulum-Golgi intermediate compartment(ERGIC); natural killer (NK)

Appendix A

Table A1. List of drugs with anticancer effects or used for best supportive cancer care, in clinical studies for the treatment of COVID-19.
Table A1. List of drugs with anticancer effects or used for best supportive cancer care, in clinical studies for the treatment of COVID-19.
Anticancer DrugViral—Host TargetsMechanism of ActionTested in Clinical TrialsNCT IdentifierCombinationStatusPhaseEligible PopulationPrimary End-PointSource (20 May 2021)
AcalabrutinibBTKInhibits the activity of BTK and prevents the activation of the B-cell antigen receptorUnited statesNCT04380688-CompletedPhase 2COVIDCOVID-19 infectionOccurrence of Adverse Events and Serious Adverse Events[10]
Several locationsNCT04346199-CompletedPhase 2COVID-19 infectionSubject alive and free of respiratory failure
BevacizumabVEGFVascular permeability inhibitionYes (France and China)NCT04275414-CompletedPhase 2Severe lung disease or critical diseaseChange of PaO2 to FiO2 ratio[10]
NCT04344782-Not yet recruitingPhase 2Severe lung diseaseNumber of patients who avoid mechanical-assisted ventilation
NCT04305106-RecruitingNot applicableDisease requiring O2-supportTime to clinical improvement
Bicalutamide Downregulates TMPRSS2Binding of androgen receptor YesNCT04509999-RecruitingPhase 3COVID-19 infection, confirmedCOVID-19 symptom relief[9]
NCT04652765camostatRecrutingPhase 1COVID-19 infection, confirmedReduce number of participants requiring hospitalization
CamrelizumabImmune homeostasisPD-1/PD-L1 pathwayYes (China)ChiCTR2000029806-RecruitingNot applicableCOVID-19 infectionProportion of patients with[10]
Blockadea lung injury score
-reduction
CarrimycinInhibit the replication of SARS-CoV-2 in the<break/>cells Inhibits mTOR pathwayNot providedNCT04286503-Not yet recrutingPhase 4 COVID-19 infectionFever to normal time[11]
NCT04672564-RecrutingPhase 3 Patient with SARS-CoV-2 infectionPercentage of patients alive without need for supplemental oxygen and ongoing in patient-medical care
DecitabineNucleic Acid Synthesis Inhibitor Nucleic acid synthesis inhibitor Yes (USA)NCT04482621-RecrutingPhase 2COVID infectionClinical improvement[9]
DuvelisibPI3K inhibitionImmune homeostasis restoration and viral replication inhibitionYes (USA)NCT04372602-RecrutingPhase 2Critical diseaseOverall survival[10]
NCT04487886-RecrutingPhase 2severe COVID-19 who do not require mechanical ventilationReduce overall necessity of ventilation
EnsifentrineHigh selectivity for PDE3 and PDE4 over other enzymes and receptors to minimize off-target effectsDual inhibitor of phosphodiesterase 3 (PDE3) and 4 (PDE4)United statesNCT04527471NoneActive, not recrutingPhase 2 SARS-CoV-2 infectionProportion of patients with recovery[11]
Enzalutamide reduce androgen driven morbidity in COVID-19Competitive binder of androgens SwedenNCT04475601-RecrutingPhase 2 SARS-CoV-2 infectionTime to worsening of disease[9]
EtoposideTopoisomerase II Inhibits DNA synthesis by forming a complex with topoisomerase II and DNAUnited statesNCT04356690-Active, not yet RecrutingPhase 2 Confirmed COVID-19 infectionChange in pulmonary status[9]
FN-B1AJak1 and Tyk2 Jak1 and Tyk2 UKNCT04385095-RecruitingPhase 2COVID-19 infectionClinical Improvement[10]
Jak1 and Tyk2 Several locationsNCT04315948Lopinavir, ritonavirActive, not yet RecruitingPhase 3COVID-19 infectionPercentage of subjects reporting severity
-IranNCT04350671Hydroxychloroquine, lopinavir, ritonavirEnrolling by invitationPhase 4COVID-19 infectionReduce Mortality
-IrnaNCT04350684Hydroxychloroquine, lopinavir, ritonavir, umifenovirEnrolling by invitationPhase 4COVID-19 infectionTime to clinical improvement
-Several locationsNCT02735707MultifactorialRecruitingPhase 4COVID-19 infectionAll-cause mortality
Genistein Inhibition of<break/>both transcription nuclear factor-κB (NF-κB) activation and chemokine-8 secretion Triggers the ER stress through upregulation of glucose-regulated protein 78 (GRP78) expression United statwaNCT04482595-RecrutingPhase 2 Patients hospitalized for COVID-19Change in Diffusing capacity of the lungs for carbon monoxide[9]
IbrutinibInhibition of the Bruton tyrosine kinaseProtection against immune-induced lung injuryYes (USA)NCT04375397-Active, not yet RecruitingPhase 2Hospitalised patients with severe pneumoniaRespiratory failure-free survival rate, overall survival [10]
NCT04439006-RecrutingPhase 2Patients Requiring HospitalizationPatients with diminished respiratory failure and death
IFNJak1 and Tyk2 Jak1 and Tyk2 CanadaNCT04354259-RecruitingPhase 2COVID-19 infectionNegative SARS-CoV-2 RNA on nasopharyngeal swab[10]
Jak1 and Tyk2 Jak1 and Tyk2 ChinaNCT04331899-Active, Not yet recruitingPhase 2COVID-19 infection
IFN beta 1bJak1 and Tyk2 Jak1 and Tyk2 Hong kongNCT04647695RemdesivirRecruitingPhase 2high risk of clinical deteriorationClinical improvement[10]
NCT04494399ribavirinRecruitingPhase 2COVID-19 infectionReduce hospitalisation
IFN-A2Bactivate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2) activate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2) United StatesNCT04349410-CompletedPhase 2/3CoVid-19 infectionImprovement in FMTVDM Measurement with nuclear imaging[10]
NCT04379518-RecruitingPhase 1/2Patients with cancer and mild or moderate symptomatic infectionIncidence of adverse events
IFN-B1A/BJak1 and Tyk2 Jak1 and Tyk2 IrnanNCT04343768Hydroxychloroquine, lopinavir, ritonavirCompletedPhase 2COVID-19 infectionTime to clinical improvement[10]
IFN-B1BJak1 and Tyk2 Jak1 and Tyk2 Hong kongNCT04350281Hydroxychloroquine, lopinavir, ritonavirCompletedPhase 2COVID-19 infectionTime to negative NPS viral load[10]
Jak1 and Tyk2 Jak1 and Tyk2 Hong kongNCT04276688Ribavirin, lopinavir, ritonavirCompletedPhase 2COVID-19 infectionTime to negative NPS
ImatinibBCR/ABL kinase inhibitionBlockade of cell entry and endosomal traffickingYes (France, Spain and USA)NCT04357613-Not yet RecruitngPhase 2Hospitalised patientsRate of prevented severe disease worsening[10]
InterferonJak1 and Tyk2 Jak1 and Tyk2 ChinaNCT04291729Danoprevir, ritonavirCompletedPhase 4COVID-19 infectioRate of composite adverse outcome[10]
LenalidomideImmunomodulatory agent substrate specificity of the CRL4CRBN E3 ubiquitin ligase SpainNCT04361643-Not yet recrutingPhase 4 COVID-19 infectionClinical improvement[10]
LeronlimabDisruption of the CCL5/RANTES-CCR5 pathwayImmune homeostasis restorationYes (USA)NCT04343651-Active, not recruitngPhase 2Mild/moderate diseaseClinical improvement[10]
NCT04347239-RecrutingPhase 2Severe lung disease or critical diseaseOverall survival[10]
Masitinib directly binds to the active site of 3CLpro Tyrosine kinase inhibitor Yes (France)NCT04622865IsoquercetinRecrutitingPhase 2 COVID 19 diagnosisClinical status of patients at day-15[9]
Melphalan anti-inflammatory responseInhibition of DNA and RNA synthesis by realizing an alkylating peptide Yes (Russian Federation)NCT04380376-RecrutitingPhase 2 COVID 19 diagnosisThe changes of COVID Ordinal Outcomes Scale[9]
MethotrexateImmunomodulatory agent inhibition of folate dependent pathways leading to inhibition of DNA synthesisFranceNCT04481633HydroxychloroquineRecruitingNot applicable COVID-19 infectionRate of patients with positive anti-COVID19 serology[10]
Nasal IFN-A1BJak1 and Tyk2 Jak1 and Tyk2 ChinaNCT04320238Anti-thymosinRecruitingPhase 3Formally serving medical staff in Taihe Hospitalnew-onset COVID-19[10]
NivolumabPD-1/PD-L1 pathway blockadeImmune homeostasis restorationYes (France and China)NCT04343144-Not yet recruitingPhase 2Disease requiring O2-supportTime to clinical improvement[10]
NCT04413838-Not yet recruitingPhase 2Obese individualsEfficacy and safety[10]
NCT04356508-Not yet recruitingPhase 2Clinically stable patients with mild or moderate disease and asymptomatic patientsViral clearance kinetics[10]
OpaganibInhibition of sphingosine kinase-2Anti-inflammatory and antiviral propertiesYes (Israel)NCT04414618-CompletedPhase 2Disease requiring O2-supportMeasurement of the daily O2 requirements[10]
NCT04467840-RecrutingPhase 2 and 3Disease requiring O2-supportReduce Intubation and mechanical ventilation
NCT04435106-Completed-severe COVID-19 who required oxygen support via high-flow nasal cannulaMeasure the time to weaning from high-flow nasal cannula and
Measure the time to breathing ambient
NCT04502069-Withdrawn (To be replaced with a randomized placebo-controlled study.)Phase 1 and 2Pneumonia Requiring OxygenTime to breathing room air
PD-1 blocking antibodyPD-1Can prevent the tumor cell from binding PD-1 Not providedNCT04268537-Not yet recruitingPhase 2COVID-19 infectionlung injury score[10]
Peg-IFN-L1Jak1 and Tyk2 Jak1 and Tyk2 United statesNCT04343976-Enrolling by invitationPhase 2COVID-19 infectioNegative SARS-CoV-2 RNA on nasopharyngeal swab[10]
Peg-IFN-L1AJak1 and Tyk2 Jak1 and Tyk2 United statesNCT04388709-Withdrawn (Due to the number of competing trials at their site, the study team has closed enrollment and withdrawn this trial.)Phase 2COVID-19 infectionNumber of participants with resolution of hypoxia[10]
United statesNCT04344600-Not yet recruitingPhase 2COVID-19 infectionProportion of participants with no evidence of SARS-CoV-2 infection
PembrolizumabPD-1/PD-L1 pathway blockadeImmune homeostasis restorationYes (Spain)NCT04335305TocilizumabRecruitingPhase 2Severe lung disease or critical diseasePercentage of patients with normalisation of SpO2 ≥96% on room air[10]
PlitidepsinBlockade of eEF1AInterference with the viral cycleYes (Spain)NCT04382066-CompletedPhase 1Hospitalised patientsFrequency of occurrence of Grade 3 or higher AEs[10]
SelinexorBlockade of nucleocytoplasmic transportAntiviral and anti-inflammatory propertiesYes (USA, France, Austria, Spain and United Kingdom)NCT04355676-Withdrawn (No participants enrolled)Phase 2Hospitalised patients with moderate or severe diseasePercentage of participants with at least a two-point improvement in the ordinal scale[10]
NCT04349098-CompletedPhase 2Hospitalised patients with severe diseaseImprovement
NCT04534725-RecruitingPhase 3received cancer related treatmentCOVID-19 Prevention and Treatment in Cancer
SFX-01 up-regulates the Nrf2 pathway Up-regulates the Nrf2 pathway UK + Evgen Pharma- -Enrolment begins in July (results are expected in 2021) Phase 2/3 -Efficacy at treating ARDS [11]
SiltuximabInterleukin-6 Interleukin-6 SpainNCT04329650-RecruitingPhase 2Hospitalized patientProportion of patients requiring ICU admission at any time[11]
ItalyNCT04322188-Completed-COVID-19 infectionmortality in siltuximab treated patients
BelgiumNCT04330638AnakinraActive, not recrutingPhase 3COVID-19 infectionTime to Clinical Improvement
Saudi ArabiaNCT04486521tocilizumabRecruiting-COVID-19 infectionVentilator-Free Days
Tamoxifen Decreased the PGE2 production Compete with 17β-estradiol (E2) at the receptor site EgyptNCT04568096-Not yet recrutingPhase 2 Adult SARI patients with COVID-19 infectionLung injury score[9]
TetrandrineAbility to block the two-pore channel 2 (TPC2) Checkpoint inhibitor of the cell cycle ChinaNCT04308317-Enrolling by invitationPhase 4 COVID-19 infectionSurvival rate[10]
Thalidomideinhibition of inflammatory cytokine production Inhibit the production of interleukin (IL)-6,ChinaNCT04273529-Not yet recruitingPhase 2COVID-19 infectionTime to Clinical recovery[10]
ToremifeneInteraction with coronavirus proteinsInhibition of viral membranes fusion with host cell endosomes? (Not provided)NCT04531748MelatoninWithdrawn (Funding)Phase 2-Clinical improvement[10]
ZanubrutinibInhibition of the Bruton tyrosine kinaseProtection against immune, lethal and sepsis-induced pulmonary injuriesYes (USA)NCT04382586-CompletedPhase 2Disease requiring O2-supportRespiratory failure-free survival rate[10]
ZotatifinBlockade of eIF4AInhibition of protein biogenesisNoNCT04632381-Not yet recruitingPhase 1--[10]

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Figure 1. Principal targets of the anticancer drugs or drugs used for breast cancer supportive care, repurposed in clinical trials for COVID-19, adapted from BioRender templates [38].
Figure 1. Principal targets of the anticancer drugs or drugs used for breast cancer supportive care, repurposed in clinical trials for COVID-19, adapted from BioRender templates [38].
Pharmaceutics 13 00815 g001
Table 1. Anticancer drugs in clinical trials for COVID-19: Interferon-based therapies.
Table 1. Anticancer drugs in clinical trials for COVID-19: Interferon-based therapies.
Anticancer DrugViral—Host TargetsMechanism of ActionCombinationPrimary End-PointSource (20 May 2021)
IFNJak1 and Tyk2 Jak1 and Tyk2 -Negative SARS-CoV-2 RNA on a nasopharyngeal swab[10]
Jak1 and Tyk2 Jak1 and Tyk2 -
IFN-B1AJak1 and Tyk2 Jak1 and Tyk2 -Clinical Improvement[10]
Jak1 and Tyk2 Lopinavir, ritonavirPercentage of subjects reporting severity
Hydroxychloroquine, lopinavir, ritonavirReduce Mortality
Hydroxychloroquine, lopinavir, ritonavir, umifenovirTime to clinical improvement
MultifactorialAll-cause mortality
IFN beta 1bJak1 and Tyk2 Jak1 and Tyk2 RemdesivirClinical improvement[10]
ribavirinReduce hospitalisation
IFN-A2Bactivate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2) activate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2) -Improvement in FMTVDM Measurement with nuclear imaging[10]
-Incidence of adverse events
IFN-B1A/BJak1 and Tyk2 Jak1 and Tyk2 Hydroxychloroquine, lopinavir, ritonavirTime to clinical improvement[10]
IFN-B1BJak1 and Tyk2 Jak1 and Tyk2 Hydroxychloroquine, lopinavir, ritonavirTime to negative NPS viral load[10]
Jak1 and Tyk2 Jak1 and Tyk2 Ribavirin, lopinavir, ritonavirTime to negative NPS
Table 2. Anticancer drugs in clinical trials for COVID-19: Anti-cytokine agents.
Table 2. Anticancer drugs in clinical trials for COVID-19: Anti-cytokine agents.
Anticancer DrugViral—Host TargetsMechanism of ActionCombinationPrimary End-PointSource (20 May 2021)
Thalido-mideInhibition of inflammatory
cytokine production
Inhibit the producti-on of interleukin
(IL)-6
-Time to clinical recovery[10]
SiltuximabInterleukin-6 Interleukin-6 -The proportion of patients Requiring ICU admission at any time
-Mortality in siltuximab treated patients[11]
AnakinraTime to clinical improvement
tocilizumabVentilator-free days
Table 3. Anticancer drugs in clinical trials for COVID-19: Immune-checkpoint inhibitors.
Table 3. Anticancer drugs in clinical trials for COVID-19: Immune-checkpoint inhibitors.
Anticancer DrugViral—Host TargetsMechanism of ActionCombinationPrimary End-PointSource (20 May 2021)
PD-1 blocking antibodyPD-1 Can prevent the tumor cell from binding PD-1 -Lung injury score[10]
NivolumabPD-1/PD-L1 pathway blockadeImmune homeostasis restoration-Time to clinical improvement[10]
-Efficacy and safety[10]
-Viral clearance kinetics[10]
PembrolizumabPD-1/PD-L1 pathway blockadeImmune homeostasis restorationTocilizumabPercentage of patients with the normalisation of SpO2 ≥96% in room air[10]
Table 4. Anticancer drugs in clinical trials for COVID-19: Hormone therapy.
Table 4. Anticancer drugs in clinical trials for COVID-19: Hormone therapy.
Anticancer DrugViral—Host TargetsMechanism of ActionCombinationPrimary End-PointSource (6 February 2021)
Bicalutami-deDownregulates TMPRSS2Binding of androgen receptor-COVID-19 symptom relief[9]
CamostatReduce number of participants requiring hospitalization
Enzalutami-de Reduce androgen driven morbidity in COVID-19 Competitive binder of androgens -Time to worsening of disease[9]
ToremifeneInteraction with coronavirus proteinsInhibition of viral membranes fusion with Host cell endosomesMelatoninClinical improvement[10]
Tamoxifen Decreased the PGE2 production Compete with 17β-estradiol (E2) at the receptor site -Lung injury score[9]
Table 5. Anticancer drugs in clinical trials for COVID-19: The inhibitor of elongation factor 1A and the eukaryotic initiation factor 4A.
Table 5. Anticancer drugs in clinical trials for COVID-19: The inhibitor of elongation factor 1A and the eukaryotic initiation factor 4A.
Anticancer DrugViral—Host TargetsMechanism of ActionCombinationPrimary End-PointSource (20 May 2021)
PlitidepsinBlockade of eEF1AInterference with the viral cycle-Frequency of occurrence of Grade 3 or higher AEs[10]
ZotatifinBlockade of eIF4AInhibition of protein biogenesis-[10]
Table 6. Anticancer drugs in clinical trials for COVID-19: Blockade of kinase cascades.
Table 6. Anticancer drugs in clinical trials for COVID-19: Blockade of kinase cascades.
Anticancer DrugViral—Host TargetsMechanism of ActionCombinationPrimary End-PointSource (20 May 2021)
DuvelisibPI3K inhibitionImmune homeostasis restoration and viral replication inhibition-Overall survival[10]
-Reduce overall necessity of ventilation
ZanubrutinibInhibition of the Bruton tyrosine kinaseProtection against immune, lethal and sepsis-induced pulmonary injuries-The respiratory failure-free survival rate[10]
CarrimycinInhibit the replication of SARS-CoV-2 in
the cells
Inhibits mTOR pathway-Fever to normal time[11]
-Percentage of patients alive without the need for supplemental oxygen and ongoing in patient-medical care
IbrutinibInhibition of the Bruton tyrosine kinaseProtection against immune-induced lung injury-The respiratory failure-free survival rate, overall survival[10]
-Patients with diminished respiratory failure and death
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Costa, B.; Vale, N. A Review of Repurposed Cancer Drugs in Clinical Trials for Potential Treatment of COVID-19. Pharmaceutics 2021, 13, 815. https://doi.org/10.3390/pharmaceutics13060815

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Costa B, Vale N. A Review of Repurposed Cancer Drugs in Clinical Trials for Potential Treatment of COVID-19. Pharmaceutics. 2021; 13(6):815. https://doi.org/10.3390/pharmaceutics13060815

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Costa, Bárbara, and Nuno Vale. 2021. "A Review of Repurposed Cancer Drugs in Clinical Trials for Potential Treatment of COVID-19" Pharmaceutics 13, no. 6: 815. https://doi.org/10.3390/pharmaceutics13060815

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