AstraZeneca Initiates Global CALAVI Trial of Calquence for Severe COVID-19 with Cytokine Storm

From Jike Yao Wen

On April 14, AstraZeneca announced the initiation of a randomized, global clinical trial to evaluate the potential of Calquence (acalabrutinib) in treating severely ill patients with COVID-19 infection accompanied by an excessive immune response (cytokine storm). The trial design is based on robust scientific evidence supporting the role of the Bruton’s tyrosine kinase (BTK) pathway in the production of inflammatory cytokines, as well as on encouraging early clinical data. Calquence is a next-generation, highly selective BTK inhibitor currently used to treat certain types of blood cancers.

The CALAVI trial is based on early clinical data for Calquence, which suggested that inflammation reduction caused by BTK inhibition appears to lower the severity of COVID-19-induced respiratory distress. The aim of the trial is to evaluate the efficacy and safety of adding Calquence to best supportive care (BSC) in order to reduce mortality and the need for assisted ventilation in patients with life-threatening symptoms of COVID-19.

CALAVI is a large-scale, randomized, open-label, multicenter, global clinical trial employing a two-part, patient-centric design to evaluate the efficacy and safety of Calquence in combination with best supportive care (BSC) versus BSC alone in patients hospitalized for respiratory complications. The trial was developed in record time to accelerate data collection and analysis. Part 1 involves randomization (2:1) to assess the addition of Calquence to BSC compared with BSC alone in non-intensive care unit (non-ICU) hospitalized patients with COVID-19. Part 2 evaluates the addition of Calquence to BSC in a cohort of patients with more severe respiratory complications in the ICU. The primary endpoint is the use of assisted ventilation or death. The CALAVI trial is expected to begin enrolling participants in the United States and several European countries within the coming days. Dr. Wyndham H. Wilson of the National Cancer Institute (NCI) will serve as the principal investigator, and Dr. Louis M. Staudt will serve as the senior investigator.

José Baselga, Executive Vice President of Oncology R&D at AstraZeneca, stated, “Through this trial, we are responding to novel insights from the scientific community and hope to demonstrate that adding Calquence to best supportive care can reduce the need for mechanical ventilation in patients and improve their survival rates. This marks the fastest launch of any clinical trial in AstraZeneca’s history.” Dr. Louis M. Staudt, Director of the Lymphoid Malignancies Branch at the National Cancer Institute (NCI), commented, “Given the role of BTK protein in regulating inflammation, inhibiting BTK with acalabrutinib has the potential to provide clinical benefit for patients with advanced COVID-19-related lung disease. As with all new treatments, it is essential to collect data from clinical trials to determine the optimal and safest treatment regimen for patients.”

Calquence is a next-generation selective BTK inhibitor. Calquence binds covalently to BTK, thereby inhibiting its activity. In B cells, BTK signaling leads to the activation of pathways essential for B-cell proliferation, trafficking, chemotaxis, and adhesion. Calquence (acalabrutinib) is approved in the United States and several other countries for the treatment of adult patients with chronic lymphocytic leukemia (CLL). Additionally, Calquence is indicated for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy in the United States and several other countries.

In pulmonary macrophages, BTK is a key regulator of the production of various cytokines and chemokines, including TNF-α, IL-6, IL-10, and MCP-1. Inhibition of BTK reduces the production of these cytokines; therefore, it represents a promising strategy for mitigating respiratory complications in COVID-19. Evidence suggests that dysregulated BTK-dependent macrophage signaling may be a central mechanism underlying the hyperinflammatory response to SARS-CoV-2 and plays a role in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS). In macrophages, TLR3, TLR7, and TLR8 recognize single-stranded RNA from viruses such as SARS-CoV-2 and initiate signaling through BTK-dependent activation of NF-κB and IRF3, triggering the production of multiple inflammatory cytokines and chemokines. Supporting the role of BTK inhibition, therapeutic inhibition of BTK in patients with lymphoid malignancies has been shown to reduce pro-inflammatory cytokines and chemokines. Similar results have been observed in murine influenza models, where BTK inhibitors reduced these inflammatory mediators and protected mice from lethal acute lung injury.

References:

[1] AstraZeneca initiates CALAVI clinical trial with Calquence against COVID-19. Retrieved 2020-04-14, from https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-initiates-calavi-clinical-trial-with-calquence-against-covid-19.html

Original Title: AstraZeneca’s Anti-Cancer Drug Shows Initial Efficacy in Treating COVID-19, Large-Scale Clinical Trials to Be Launched

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