Clinical trial NCT04534725: COVID-19 Prevention and Treatment in Cancer; a Sequential Multiple Assignment Randomised Trial;
Official title: COVID-19 Prevention and Treatment in Cancer; a Sequential Multiple Assignment Randomised Trial; C-SMART Study.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cancer
Covid19
Respiratory Viral Infection
Keywords: COVID-19
cancer
Lead sponsor: Peter MacCallum Cancer Centre, Australia
Sponsor class: OTHER
First posted: 2020-09-01
Enrollment: 441
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: the study uses a SMART design. (sequential multiple arm randomised trial) meaning that participants can enter into the study and progress through the subsequent arms if they meet the additional eligibility criteria (for instance, pre-covid \> post exposure \> develop moderate infection \> infection becomes severe) it is important to note that participants can enter into the study at any point and do not have to transition into the other arms
Primary purpose: TREATMENT

Brief summary: A multi-centre Australian trial with four arms aims to evaluate several different immune modulating drugs for prevention and treatment of COVID-19 specifically in the cancer population.

ARM 1 is evaluating the effect of interferon-alpha (vs placebo) on the incidence of COVID-19 infection in cancer patients with no COVID-19 infection or no known COVID-19 positive contacts.

ARM 2 is evaluating the effect of interferon-alpha (vs placebo) on the incidence of COVID-19 infection in cancer patients with confirmed exposure to COVID-19 virus.

ARM 3 is evaluating the effect of Selinexor (vs placebo) on the incidence of COVID-19 infection in cancer patients with moderate COVID-19 infection.

ARM 4 is evaluating the effect of Lenzilumab (vs placebo) on the treatment of COVID-19 infection in cancer patients with severe COVID-19 infection.

Participants may become eligible and transition to different arms and treatments if they become exposed to COVID-19 or are hospitalised with an active moderate/severe COVID-19 infection.

It is hoped this research will provide insight into the best practice for prevention and treatment of COVID-19 in cancer patients as emerging standard of care measures are not always suitable to this especially vulnerable population.


Eligibility criteria: Inclusion Criteria:

* ARM 1:

  1. Age equal to or greater than 18 years old
  2. Any haematological or solid tumour
  3. Signed written and verbal informed consent
  4. Willingness to inform the study nurse/co-ordinator of COVID-19 testing
  5. Willingness to perform a self-collect nose/throat swab

ARM 2

1. Age equal to or greater than 18 years old.
2. Any haematological or solid tumour
3. Signed written and verbal informed consent
4. Have been exposed to a known COVID-19 case within the last 72 hours, defined by the current Department of Health and Human services such as household contact, 15 minutes of face to face exposure, 2 hours in close space.
5. Willingness to inform the study nurse/co-ordinator of COVID-19 testing
6. Willingness to perform a self-collect nose/throat swab

ARM 3 1. Age equal to or greater than 18 years of age. 2. Any haematological or solid tumour 3. Current or within the last 12 months received cancer related treatment such as chemotherapy, radiotherapy or targeted small molecule, cellular therapy or immune-modulating therapy 4. Signed written and verbal informed consent 5. Laboratory confirmation of SARS-CoV-2 by PCR as per local laboratory assays 6. Hospitalised 7. Symptoms of COVID-19 such as:

1. Fever equal to or greater than 38 degrees Celsius OR
2. Tachypnoea respiratory rate equal to or greater than 20 breaths/min OR
3. Pulse Oxygen saturation (SpO2) equal to or less than 94% 8. Concurrent standard of care antimicrobials, antivirals are allowed. 9. Female and male patients of child bearing potential will use highly effective contraception. In female child bearing potential participants a negative urine pregnancy test will be required.

   ARM 4
   1. Age equal to or greater than 18 years of age.
   2. Any haematological or solid tumour
   3. Current or within the last 12 months received cancer related treatment such as chemotherapy, radiotherapy or targeted small molecule, cellular therapy or immune-modulating therapy
   4. Signed written and verbal informed consent by participant or proxy capable of giving consent
   5. Laboratory virological confirmation of SARS-CoV-2 by PCR as per local laboratory assays and COVID-19 diagnosis prior to randomisation
   6. Hospitalised but has not required mechanical ventilation
   7. Pneumonia diagnosed by chest x-ray or computed tomography (CT) revealing infiltrates consistent with pneumonia and SpO2 equal to or less than 94% on room air or requires low-flow oxygen supplementation or requires high-flow oxygen supplementation or non-invasive positive pressure ventilation (NIPPV).
   8. Has not participated in other clinical trials for COVID-19 using an immunomodulating monoclonal antibody or kinase inhibitor. Note that participants on dexamethasone, corticosteroids, remdesivir, convalescent plasma and/or hydroxychloroquine with or without azithromycin are not excluded from the study. Agents that have received emergency use authorization and/or are considered by the study site to be standard treatment at the institution for COVID-19 are permitted provided the agent is not an immunomodulating monoclonal antibody or kinase inhibitor. Participation in clinical trials with remdesivir or convalescent plasma is permitted provided that all other eligibility criteria are met.
   9. Females of childbearing potential must have a negative serum or urine pregnancy test at screening/baseline. Women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for 5 months following their last dose of study drug.

   Exclusion Criteria:
   * ARM 1

     1. Previous diagnosis of COVID-19 (microbiologically proven, either symptomatic or asymptomatic)
     2. Have been exposed to a known COVID-19 case within the last 72 hours, defined by the current Department of Health and Human services such as household contact, 15 minutes of face to face exposure, 2 hours in close space.
     3. Any contra-indication to intra-nasal IFN-a such as severe nasal bleeding requiring intervention, nasal malignancy, nasal deformity, radiotherapy to the nasopharynx and/or oropharynx
     4. Pregnant or breast-feeding women, or women who wish to become pregnant during the course of the study
     5. Participant unable to return for regular follow-up
     6. Life expectancy of less than 4 months
     7. Participant already included in another intervention study on the prevention of COVID-19
     8. Currently unwell with influenza-like symptoms - if participant is found to be COVID-19 negative and becomes asymptomatic, they can be reconsidered for participation

   ARM 2
   1. Previous diagnosis of COVID-19 (microbiologically proven, either symptomatic or asymptomatic)
   2. Any contra-indication to intra-nasal IFN-a such as severe nasal bleeding requiring intervention, nasal malignancy, nasal deformity, radiotherapy to the nasopharynx and/or oropharynx
   3. Pregnant or breast-feeding women, or women who wish to become pregnant during the course of the study
   4. Patient unable to return for follow-up
   5. Life expectancy of less than 1 month
   6. Patient already included in another intervention study on the prevention of COVID-19
   7. Currently unwell with influenza-like symptoms

   ARM 3
   1. Unable to take oral medication
   2. Any known allergic reactions to selinexor or concomitant medication-related contra-indications to selinexor.
   3. Severe critical COVID-19 infection defined as:

      1. Requiring invasive or non-invasive mechanical ventilation, ECMO
      2. Anticipated unlikely to survive within 48 hours
   4. In the opinion of the investigator and primary oncologist, participation in the study would not be in the best interests of the participant
   5. Severe renal impairment defined as creatinine clearance (CrCL) \< 20ml/min as calculated using the Cockcroft Gault formula
   6. Severe hepatic impairment defined as aspartate transaminase (AST) or alanine transaminase (ALT) \> 5 x upper limit of normal (ULN)

   ARM 4

   1. Invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) 2. History of pulmonary alveolar proteinosis (PAP). 3. Women of childbearing potential who are pregnant or breastfeeding. 4. Known hypersensitivity to lenzilumab or any of its components. 5 .Use of any FDA-approved anti-IL-6 therapy (eg. tocilizumab, sarilumab, siltukimab), anti-IL-1 therapy (eg. anakinra, canakinumab) or kinase inhibitor (eg.baracitinib, ibrutinib, acalabrutinib) therapy to treat COVID-19 within 8 weeks prior to randomization. Any live vaccine within 8 weeks prior to randomisation. Note that subjects receiving other FDA-approved immunomodulators to treat underlying autoimmune disorders such as rheumatoid arthritis, psoriasis, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, atopic dermatitis, multiple sclerosis, etc. would not be excluded. Participants on corticosteroids or dexamethasone are not excluded from the study. Note: Participants on convalescent plasma, remdesivir and/or hydroxychloroquine with or without azithromycin are not excluded from the study.

   6. Use of GM-CSF agents (e.g., sargramostim) within 8 weeks prior to randomisation.

   7. Expected survival \< 24h in the opinion of the investigator. 8. Any condition that, in the opinion of the investigator, is likely to interfere with the safety and efficacy of the study treatment or puts the subject at unacceptably high risk from the study.

   9. Participation in another interventional study of COVID-19

Primary outcomes:
measure: Incidence of COVID-19 in cancer patients using interferon-alpha as prophylaxis without known positive contact with COVID-19 (COVID-19 confirmed by qPCR from respiratory swab)
timeFrame: 3 months from baseline.
measure: incidence of any upper or lower community acquired respiratory viral infection assessed using local standard of care testing
timeFrame: 3 months from baseline.
measure: incidence of COVID-19 when Interferon alpha is given as post-exposure prophylaxis with a known positive contact or exposure with COVID-19. COVID-19 confirmed by qPCR from respiratory swab .
timeFrame: 28 days from baseline
measure: incidence of any upper or lower community acquired respiratory viral infection assessed using local standard of care testing
timeFrame: 28 days from baseline
measure: incidence of death and/or need for invasive or non-invasive ventilation. assessed using medical records
timeFrame: 60 days from baseline
measure: time to clinical improvement or discharge from hospital assessed using medical records
timeFrame: 28 days from baseline
Secondary outcomes:
measure: ARM 1: Duration of acute respiratory/ILI symptoms in case of confirmed respiratory infection during the study period. Assessed using patient symptom Diary PRO tool
timeFrame: 120 days from baseline
measure: ARM 1: Time to diagnosis of COVID-19 in case of confirmed COVID-19 diagnosed during the study period (days). Assessed using patient medical records
timeFrame: 120 days from baseline
measure: ARM 1: Time to diagnosis of other respiratory viral infection in case of confirmed other respiratory viral infection diagnosed during the study period (days). assessed using patient medical records
timeFrame: 120 days from baseline
measure: ARM 1: Illness severity in case of confirmed COVID-19 diagnosed during the study period using WHO clinical progression scale
timeFrame: 120 days from baseline
measure: ARM 1: Incidence of unplanned all-cause hospital admission during the study period. assessed using medical records
timeFrame: 120 days from baseline
measure: ARM 1: Incidence of unplanned infection-related hospital admission during the study period. assessed using medical records
timeFrame: 120 days from baseline
measure: ARM 1: Incidence of sero-conversion of SARS-CoV-2 at the end of the study period. assessed using qPCR
timeFrame: 120 days from baseline
measure: ARM 1: Incidence of death from any cause during the study period. assessed using patient medical records
timeFrame: 120 days from baseline
measure: ARM 1: Incidence of testing for COVID-19 during the study period. assessed using medical records
timeFrame: 120 days from baseline
measure: ARM 2 Duration of acute respiratory symptoms in case of confirmed COVID-19 diagnosed during the study period. assessed with PRO and medical records.
timeFrame: 28 days from baseline
measure: ARM 2: Time to diagnosis of COVID-19 in case of confirmed COVID-19 diagnosed during the study period (days). assessed using medical records
timeFrame: 28 days from baseline
measure: ARM 2: Illness severity in case of confirmed COVID-19 diagnosed during the study period. assessed using WHO clinical progression scale.
timeFrame: 28 days from baseline
measure: ARM 2: Incidence of unplanned all-cause hospital admission during the study period. assessed using medical records.
timeFrame: 28 days from baseline
measure: ARM 2: Incidence of unplanned infection-related hospital admission during the study period. assessed using medical records
timeFrame: 28 days from baseline
measure: ARM 2: Incidence of seroconversion of SARS-CoV-2 at the end of the study period. assessed using qPCR.
timeFrame: 28 days from baseline
measure: ARM 2: Incidence of testing for COVID-19 during the study period assessed using medical records
timeFrame: 28 days from baseline
measure: ARM 3: Time to clinical improvement assessed using medical records.
timeFrame: 60 days from baseline
measure: ARM 3: Illness severity of COVID-19, defined as the maximal score on the World Health Organization (WHO)'s clinical progression ordinal scale
timeFrame: 60 days from baseline
measure: ARM 3: change to clinical condition assessed with Karnofsky Performance score
timeFrame: 60 days from baseline
measure: ARM 3: Time to progression to severe COVID-19, defined by WHO ordinal scale
timeFrame: 60 days from baseline
measure: ARM 3: Time to all-cause mortality
timeFrame: 60 days from baseline
measure: ARM 3:Duration of hospitalisation assessed using medical records
timeFrame: at discharge or day 60 whichever is sooner
measure: ARM 3: Duration of COVID-19 symptoms assessed using patient reported symptom diary.
timeFrame: 60 days from baseline
measure: ARM 3: Duration of oxygen supplementation (days). assessed using medical records.
timeFrame: 60 days from baseline
measure: ARM 3: change in nasopharyngeal SARS-CoV-2 viral load shedding (assessed via qPCR)
timeFrame: 60 days from baseline
measure: ARM 3: Safety and tolerability of selinexor using relevant medical records
timeFrame: 60 days from baseline
measure: ARM 3: incidence of changes in blood results relevant to clinical improvement assessed using medical records
timeFrame: 60 days from baseline
measure: ARM 4: Incidence of all cause death by day 28 and 60
timeFrame: day 28 from baseline and day 60 from baseline
measure: ARM 4: Time to all-cause mortality
timeFrame: any time up to 60 days from baseline
measure: ARM 4: Illness severity of COVID-19, defined as the maximal score on the World Health Organization (WHO)'s clinical progression ordinal scale
timeFrame: any time up to 60 days from baseline
measure: ARM 4: Incidence of ARDS assessed using medical records
timeFrame: any time up to 60 days from baseline
measure: ARM 4: incidence of HLH. assessed using medical records
timeFrame: any time up to 60 days from baseline
measure: ARM 4: Duration of hospitalisation. assessed using hospital medical records.
timeFrame: at discharge or by day 60 whichever is sooner
measure: ARM 4: Proportion discharged from hospital. assessed using medical records
timeFrame: at discharge
measure: ARM 4: Incidence of mechanical ventilation up to day 28. assessed using medical records
timeFrame: any time up day 28 from baseline
measure: ARM 4: Ventilator-free days and proportion who did not receive invasive mechanical ventilation. assessed using medical records
timeFrame: any time up to 60 days from baseline
measure: ARM 4: Organ failure free days and proportion who did not develop organ failure. assessed using medical records.
timeFrame: any time up to 60 days from baseline
measure: ARM 4: Incidence and duration of ICU admission. assessed using medical records
timeFrame: at discharge or by day 60 from baseline.
measure: ARM 4: incidence and duration of supplemental oxygen use. assessed using medical records
timeFrame: any time up to 60 days from baseline
measure: ARM 4: Time to clinical improvement defined as National Early Warning Score 2 (NEWS2) of <2 maintained for 24 hours.
timeFrame: any time up to 60 days from baseline
measure: ARM 4: incidence of non-invasive ventilation. assessed using medical records
timeFrame: any time up to 60 days from baseline
measure: ARM 4: number of participants alive and off oxygen at day 60. assessed using medical records.
timeFrame: any time up to 60 days from baseline
measure: ARM 4: proportion of participants who had improved oxygenation for >48 hours. assessed using medical records
timeFrame: any time up to 28 days from baseline
measure: ARM 4: Incidence of adverse events based on the national cancer institute CTCAE v5. Assessed using medical records
timeFrame: any time up to day 28 from baseline.
measure: ARM 4: incidence of SAEs based on NCI CTCAE v5 assessed using medical records
timeFrame: any time up to 28 days from baseline.
measure: ARM 4: change in nasopharyngeal SARS-CoV-2 viral load shedding. assessed using qPCR.
timeFrame: any time up to day 60 from baseline
Other outcomes:
Locations:
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Fitzroy
country: Australia
facility: St Vincent's Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Austin Health
state: Victoria
Study officials:
References:
citation: Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.