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| Name | Class |
|---|---|
| Christian Medical College, Vellore, India | OTHER |
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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Topotecan | Experimental | 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:
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Topotecan | Drug | 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. |
| 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 |
| 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 |
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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:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Anand JEYASEKHARAN | Contact | +65 6779 5555 | anand_jeyasekharan@nuhs.edu.sg | |
| Anand JEYASEKHARAN | Contact |
| Name | Affiliation | Role |
|---|---|---|
| Anand JEYASEKHARAN | National University Hospital, Singapore | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Christian Medical College | Recruiting | Vellore | Tamil Nadu | 632004 | India |
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| ID | Term |
|---|---|
| D000860 | Hypoxia |
| ID | Term |
|---|---|
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D019772 | Topotecan |
| ID | Term |
|---|---|
| D002166 | Camptothecin |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
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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).
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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 |