Phase I Dose-escalation Study of Topotecan in Moderate-severe COVID-19 Patients
Overview
- Phase
- Phase 1
- Intervention
- Topotecan
- Conditions
- COVID-19 Respiratory Infection
- Sponsor
- National University Hospital, Singapore
- Enrollment
- 24
- Locations
- 1
- Primary Endpoint
- Maximal tolerable dose of Topotecan
- Last Updated
- 4 years ago
Overview
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).
Investigators
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-
- •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.
Arms & Interventions
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.
Intervention: Topotecan
Outcomes
Primary Outcomes
Maximal tolerable dose of Topotecan
Time Frame: 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 Outcomes
- Number of participant with Serious Adverse Events(Within 14 days from Topotecan administration)
- Rate of reduction in the duration of supplemental oxygen requirement in participants(1 week from administration of Topotecan)
- Rate of treatment related CTCAE grade 3/4 haematological toxicity(Up to Day 10 from Topotecan administration)
- Proportion of patients requiring ICU care(28 days from Topotecan administration)
- Proportion of patients requiring mechanical ventilation(28 days from Topotecan administration)
- Time to discharge(28 days from Topotecan administration)
- Proportion of patients with secondary infections(28 days from Topotecan administration)
- Proportion of patients who died after enrolment into trial(28 days from Topotecan administration)