Clinical trial NCT05083000: Reducing Hypoxia in Patients With Coronavirus Disease (COVID-19) Using Topotecan With Standard of Care
Official title: Phase I Dose-escalation Study of Topotecan in Moderate-severe COVID-19 Patients
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: COVID-19 Respiratory Infection
Keywords: Topotecan
hypoxia
Lead sponsor: National University Hospital, Singapore
Sponsor class: OTHER
Collaborators: name: Christian Medical College, Vellore, India
First posted: 2021-10-19
Enrollment: 24
Sex: ALL
Minimum age (years): 21
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: The dose escalation will be in a standard 3+3 dose escalation design with 0.25mg increments of Topotecan; it will begin with a single dose 0.25mg for 3 patients-expanded to another 3 if no toxicities are seen. Subsequent dose levels will be 2 doses of 0.25mg, a single dose of 0.5mg and then 2 doses of 0.5mg (maximum of 24 patients).
Primary purpose: TREATMENT

Brief summary: The primary objective of the phase 1 trial is to identify a dose of topotecan that will be safe to take forward into a Phase 2 trial, with no unexpected toxicities or drug-drug interactions with standard therapy for COVID-19. The investigators hypothesise that a single dose of low-dose Topotecan will blunt the expression of inflammatory genes in patients with moderate COVID-19, without cytotoxic side effects.

Detailed description: 4 fixed dosing levels (0.25 -0.5mg) of Topotecan will be evaluated in this trial, using sub-cytotoxic doses of Topotecan which are well below typical chemotherapy levels and shown not to cause myelosuppression in previously tested populations. The dose escalation will be in a standard 3+3 dose escalation design with 0.25 mg increments of Topotecan. The study aims to establish the recommended phase 2 dose (RP2D) of Topotecan in hypoxic patients with moderate to severe COVID-19.The RP2D is defined as the maximum safe dose at which 3 or more patients are found to have clinically relevant concentrations of Topotecan in the blood stream, without reaching anti-cancer concentrations in plasma (defined as Area under the curve (AUC)\>150000) and without causing Grade 2/3/4 neutropenia (CTCAE5).

Eligibility criteria: Inclusion Criteria:

* Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by at least 1 positive Polymerase Chain Reaction (PCR) test
* Moderate COVID as evidenced by Oxygen saturation \<93% on room air (or \<88% if prior CLD)
* Admission to emergency department for monitoring and/or supportive care:
* The following biochemical markers:
* Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. Platelets ≥ 100 x 109/L, Haemoglobin ≥ 9x 109/L.
* Bilirubin \< 1.5 times upper limit of normal (ULN). Alanine aminotransferase (ALT) and Aspartate Aminotransferase (AST) \< 2.5 times ULN.
* Calculated creatinine clearance of ≥ 30ml/min calculated using the formula of Cockcroft and Gault: (140-age) x mass (kg)/)72x creatinine mg/dl); multiple by 0.85 if female.
* Laboratory features of cytokine release, as defined by any 1 of the following:

  i. C-reactive protein (CRP)\> 75mg/L ii. Lactate Dehydrogenase (LDH) \> ULN iii. D-dimer \> 1.0 mg/L iv. Ferritin \> 500ng/ml v. Elevated Interleukin-6 levels

Exclusion Criteria:

* Patients requiring mechanical ventilation
* Any immunosuppressive medication including chemotherapy(excluding steroids) administered concurrently or within last 14 days.
* Patients with uncontrolled diabetes mellitus (HbA1C within 1 month \>8)
* Pregnancy or Breastfeeding.
* Known allergy to Topotecan. Unconjugated hyperbilirubinemia on a fasting Liver Function Test (LFT), which can indicate Gilberts Syndrome.
* Suspected active bacterial, fungal, or other infection in addition to COVID-19.
* Any condition that would, in the opinion of the Investigator, increase the risk of the participant
* by participating in the study.
* Inability to provide consent.
* Unable to comply with study procedures.

Primary outcomes:
measure: Maximal tolerable dose of Topotecan
timeFrame: 24 hours and 14 days from the time of Topotecan administration
Secondary outcomes:
measure: Rate of reduction in the duration of supplemental oxygen requirement in participants
timeFrame: 1 week from administration of Topotecan
measure: Rate of treatment related CTCAE grade 3/4 haematological toxicity
timeFrame: Up to Day 10 from Topotecan administration
measure: Number of participant with Serious Adverse Events
timeFrame: Within 14 days from Topotecan administration
measure: Proportion of patients requiring ICU care
timeFrame: 28 days from Topotecan administration
measure: Proportion of patients requiring mechanical ventilation
timeFrame: 28 days from Topotecan administration
measure: Time to discharge
timeFrame: 28 days from Topotecan administration
measure: Proportion of patients with secondary infections
timeFrame: 28 days from Topotecan administration
measure: Proportion of patients who died after enrolment into trial
timeFrame: 28 days from Topotecan administration
Other outcomes:
Locations:
city: Vellore
country: India
facility: Christian Medical College
state: Tamil Nadu
Study officials:
affiliation: National University Hospital, Singapore
name: Anand JEYASEKHARAN
role: PRINCIPAL_INVESTIGATOR
References: