COVID-19 Respiratory Infection
Conditions
Keywords
Topotecan, hypoxia
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).
Interventions
DRUGTopotecan
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.
Sponsors
Christian Medical College, Vellore, India
National University Hospital, Singapore
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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).
Eligibility
Sex/Gender
ALL
Age
21 Years to 99 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
| Proportion of patients requiring mechanical ventilation | 28 days from Topotecan administration | Number of patients requiring mechanical ventilation |
Countries
India
Contacts
Primary ContactAnand JEYASEKHARAN
Backup ContactAnand JEYASEKHARAN
Outcome results
None listed