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

Phase 1

• Conditions: COVID-19 Respiratory Infection
• Interventions: Drug: Topotecan

• Registration Number: NCT05083000
• Lead Sponsor: National University Hospital, Singapore

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).

Study Timeline

• Study Start: 2021-08-16
• Status Verified: 2021-09
• Study First Submitted: 2021-10-11
• Study First Submitted QC: 2021-10-18
• Study First Posted: 2021-10-19
• Last Update Submitted: 2021-10-27
• Last Update Posted: 2021-11-04
• Primary Completion: 2021-12-31
• Study Completion: 2022-03-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 24

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Topotecan	Topotecan	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.

Primary Outcome Measures

Name	Time	Method
Maximal tolerable dose of Topotecan	24 hours and 14 days from the time of Topotecan administration	To determine a maximal dose of Topotecan, at which less than 1 out of 3 patients exhibit anti-cancer concentrations in plasma, or have G2/3/4 neutropenia

Secondary Outcome Measures

Name	Time	Method
Rate of reduction in the duration of supplemental oxygen requirement in participants	1 week from administration of Topotecan	Determine effect of Topotecan on duration of additional oxygen requirements
Rate of treatment related CTCAE grade 3/4 haematological toxicity	Up to Day 10 from Topotecan administration	Dose limiting toxicities will be graded using CTCAE version 5.0.
Number of participant with Serious Adverse Events	Within 14 days from Topotecan administration	Serious Adverse Events experience by subject after Topotecan administration (related and unrelated).
Proportion of patients requiring ICU care	28 days from Topotecan administration	Number of patients requiring intubation/inotropic/vasopressor support
Proportion of patients requiring mechanical ventilation	28 days from Topotecan administration	Number of patients requiring mechanical ventilation
Time to discharge	28 days from Topotecan administration	Time to hospital discharge in days
Proportion of patients with secondary infections	28 days from Topotecan administration	Number of patients with secondary infections
Proportion of patients who died after enrolment into trial	28 days from Topotecan administration	Death from related and unrelated causes

Trial Locations

Locations (1)

Christian Medical College; 🇮🇳 Vellore, Tamil Nadu, India