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

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

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.

Study Overview

• Status: Recruiting
• Conditions: COVID-19 Respiratory Infection
• Intervention / Treatment: Drug: Topotecan

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 Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Anand JEYASEKHARAN; Phone Number: +65 6779 5555; Email: anand_jeyasekharan@nuhs.edu.sg
• Study Contact Backup: Name: Anand JEYASEKHARAN

Study Locations

• India
  • Tamil Nadu
    • Vellore, Tamil Nadu, India, 632004
      • Recruiting
      • Christian Medical College
      • Contact: Ajoy Oommen John; Phone Number: +91 7639195315; Email: ajoyoommenjohn@gmail.com
      • Contact: Ashish Singh; Email: todrashish@gmail.com
      • Principal Investigator: Ashish Singh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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: 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; 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.; Other Names: Topotecan hydrochloride

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Collaborators: Christian Medical College, Vellore, India
• Investigators: Principal Investigator: Anand JEYASEKHARAN, National University Hospital, Singapore

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2021
• Primary Completion (Anticipated): December 31, 2021
• Study Completion (Anticipated): March 31, 2022

Study Registration Dates

• First Submitted: October 11, 2021
• First Submitted That Met QC Criteria: October 18, 2021
• First Posted (Actual): October 19, 2021

Study Record Updates

• Last Update Posted (Actual): November 4, 2021
• Last Update Submitted That Met QC Criteria: October 27, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Topotecan; hypoxia
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Respiratory Tract Infections; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Topotecan
• Other Study ID Numbers: TOTORO1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No