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

Study Overview
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Brief Summary
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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
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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).

Official Title
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Phase I Dose-escalation Study of Topotecan in Moderate-severe COVID-19 Patients

Conditions
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COVID-19 Respiratory Infection

Intervention / Treatment
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* Drug: Topotecan


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional 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).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topotecan<br>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: IV Dexamethasone 6mg once daily for at least 5 days and not more than 10 days. IV Remdesivir 200mg loading dose on day 1 followed by 100mg once daily for 4 days. | Drug: Topotecan<br>* Topotecan hydrochloride is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitor activity. It is a well-established chemotherapeutic agent used for cancer treatment.<br>* Other names: Topotecan hydrochloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal tolerable dose of Topotecan | 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 | 24 hours and 14 days from the time of Topotecan administration | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Topotecan, hypoxia