Reducing Hypoxia in Patients With Coronavirus Disease (COVID-19) Using Topotecan With Standard of Care
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
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 Design
Arms and Interventions
| 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:
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Outcome Measures
Primary Outcome Measures
- 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
- 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
Eligibility Criteria
Criteria
Inclusion Criteria:
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by at least 1 positive Polymerase Chain Reaction (PCR) test
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Moderate COVID as evidenced by Oxygen saturation <93% on room air (or <88% if prior CLD)
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Admission to emergency department for monitoring and/or supportive care:
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The following biochemical markers:
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Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. Platelets ≥ 100 x 109/L, Haemoglobin ≥ 9x 109/L.
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Bilirubin < 1.5 times upper limit of normal (ULN). Alanine aminotransferase (ALT) and Aspartate Aminotransferase (AST) < 2.5 times ULN.
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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.
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Laboratory features of cytokine release, as defined by any 1 of the following:
- 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:
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Patients requiring mechanical ventilation
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Any immunosuppressive medication including chemotherapy(excluding steroids) administered concurrently or within last 14 days.
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Patients with uncontrolled diabetes mellitus (HbA1C within 1 month >8)
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Pregnancy or Breastfeeding.
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Known allergy to Topotecan. Unconjugated hyperbilirubinemia on a fasting Liver Function Test (LFT), which can indicate Gilberts Syndrome.
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Suspected active bacterial, fungal, or other infection in addition to COVID-19.
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Any condition that would, in the opinion of the Investigator, increase the risk of the participant
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by participating in the study.
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Inability to provide consent.
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Unable to comply with study procedures.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Christian Medical College | Vellore | Tamil Nadu | India | 632004 |
Sponsors and Collaborators
- National University Hospital, Singapore
- Christian Medical College, Vellore, India
Investigators
- Principal Investigator: Anand JEYASEKHARAN, National University Hospital, Singapore
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TOTORO1