Reducing Hypoxia in Patients With Coronavirus Disease (COVID-19) Using Topotecan With Standard of Care

National University Health System (NUHS)

Status and phase: Unknown; Phase 1

Conditions: COVID-19 Respiratory Infection

Treatments: Drug: Topotecan

Study type: Interventional

Funder types: Other

Identifiers

NCT05083000

TOTORO1

Details and patient eligibility

About

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.

Full 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).

Enrollment: 24 estimated patients

Sex: All

Ages: 21 to 99 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Sequential Assignment

Masking: None (Open label)

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24 participants in 1 patient group

Topotecan

Experimental group

Description:

Subject will receive Topotecan as a single dose or 2 consecutive doses given via intravenous (IV). The starting dose level of Topotecan is 0.25mg. Subsequent dose levels will be 2 doses of 0.25mg, a single dose of 0.5mg and then 2 doses of 0.5mg. Standard of care treatments for COVID-19 will be given together if available as per the following protocol: 1. IV Dexamethasone 6mg once daily for at least 5 days and not more than 10 days. 2. IV Remdesivir 200mg loading dose on day 1 followed by 100mg once daily for 4 days.

Treatment:

Drug: Topotecan