AstraZeneca initiates CALAVI clinical trial with Calquence against COVID-19

Trial will assess the effect of Calquence on the exaggerated immune
response of patients hospitalised with COVID-19 infection

AstraZeneca will initiate a randomised, global clinical trial to assess the potential of Calquence (acalabrutinib) in the treatment of the exaggerated immune response (cytokine storm) associated with COVID-19 infection in severely ill patients.

The trial design is based upon strong scientific evidence supporting the role of the Bruton’s tyrosine kinase (BTK) pathway in the production of inflammatory cytokines and on encouraging early clinical data. Calquence is a next-generation, highly selective BTK inhibitor currently used to treat certain types of blood cancers.

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

This large, multicentre, global, randomised trial uses a two-part patient-centric design developed in record time to accelerate data capture and analysis. Part one evaluates the addition of Calquence to BSC versus BSC alone in patients hospitalised with COVID-19 who are not in the intensive care unit (ICU). Part two evaluates the addition of Calquence to BSC in a cohort of patients in the ICU.

José Baselga, Executive Vice President, Oncology R&D, said: “With this trial we are responding to the novel insights of the scientific community and hope to demonstrate that adding Calquence to best supportive care reduces the need to place patients on ventilators and improves their chances of survival. This is the fastest launch of any clinical trial in the history of AstraZeneca.”

Louis M. Staudt, M.D., Ph.D., Chief of the Lymphoid Malignancies Branch at the National Cancer Institute, said: “Given the well documented role of the protein BTK in regulating inflammation, it is possible that inhibiting BTK with acalabrutinib could provide clinical benefit in patients with advanced COVID-19 lung disease. As with all new treatments, it will be necessary to gather data from clinical trials in order to understand the best and safest treatment options for patients.”

The CALAVI trial is expected to open for enrolment in the coming days in the US and several countries in Europe. Wyndham H. Wilson, MD, PhD, of NCI in the United States, will serve as the principal investigator of the trial. Louis M. Staudt, MD, PhD will serve as senior investigator.

INDICATION AND USAGE

CALQUENCE is a Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

CALQUENCE is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

IMPORTANT SAFETY INFORMATION ABOUT CALQUENCE® (acalabrutinib) capsules

Serious and Opportunistic Infections

Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE.

Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jiroveci pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly.

Hemorrhage

Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients.

Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding.

Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in 12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted.

Second Primary Malignancies

Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in 6% of patients.  Monitor patients for skin cancers and advise protection from sun exposure.

Atrial Fibrillation and Flutter

Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope, dyspnea) and manageas appropriate.

ADVERSE REACTIONS

The most common adverse reactions (≥ 20%) of any grade in patients with relapsed or refractory MCL were anemia,* thrombocytopenia,* headache (39%), neutropenia,* diarrhea (31%), fatigue (28%), myalgia (21%), and bruising (21%). The most common Grade ≥ 3 non-hematological adverse reaction (reported in at least 2% of patients) was diarrhea (3.2%).

*Treatment-emergent decreases (all grades) of hemoglobin (46%), platelets (44%), and neutrophils (36%) were based on laboratory measurements and adverse reactions.

Dose reductions or discontinuations due to any adverse reaction were reported in 1.6% and 6.5% of patients, respectively. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8% of patients.

The most common adverse reactions (≥ 30%) of any grade in patients with CLL were anemia,* neutropenia,* thrombocytopenia,* headache, upper respiratory tract infection, and diarrhea.

*Treatment-emergent decreases (all grades) of hemoglobin, platelets, and neutrophils were based on laboratory measurements and adverse reactions.

In patients with previously untreated CLL exposed to CALQUENCE, fatal adverse reactions that occurred in the absence of disease progression and with onset within 30 days of the last study treatment were reported in 2% for each treatment arm, most often from infection. Serious adverse reactions were reported in 39% of patients in the CALQUENCE plus obinutuzumab arm and 32% in the CALQUENCE monotherapy arm, most often due to events of pneumonia (7% and 2.8%, respectively).

Adverse reactions led to CALQUENCE dose reduction in 7% and 4% of patients in the CALQUENCE plus obinutuzumab arm (N=178) and CALQUENCE monotherapy arm (N=179), respectively. Adverse events led to discontinuation in 11% and 10% of patients, respectively. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 3.9% and 2.8% of patients in the CALQUENCE combination arm and monotherapy arm, respectively.

In patients with relapsed/refractory CLL exposed to CALQUENCE, serious adverse reactions occurred in 29% of patients. Serious adverse reactions in > 5% of patients who received CALQUENCE included lower respiratory tract infection (6%). Fatal adverse reactions within 30 days of the last dose of CALQUENCE occurred in 2.6% of patients, including from second primary malignancies and infection.

Adverse reactions led to CALQUENCE dose reduction in 3.9% of patients (N=154), dose interruptions in 34% of patients, most often due to respiratory tract infections followed by neutropenia, and discontinuation in 10% of patients, most frequently due to second primary malignancies followed by infection. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 1.3% of patients who received CALQUENCE.

DRUG INTERACTIONS

Strong CYP3A Inhibitors: Avoid co-administration with a strong CYP3A inhibitor. If a strong CYP3A inhibitor will be used short-term, interrupt CALQUENCE.

Moderate CYP3A Inhibitors: When CALQUENCE is co-administered with a moderate CYP3A inhibitor, reduce CALQUENCE dose to 100 mg once daily.

Strong CYP3A Inducers: Avoid co-administration with a strong CYP3A inducer. If a strong CYP3A inducer cannot be avoided, increase the CALQUENCE dose to 200 mg approximately every 12 hours.

Gastric Acid Reducing Agents: If treatment with a gastric acid reducing agent is required, consider using an H2-receptor antagonist or an antacid. Take CALQUENCE 2 hours before taking an H2-receptor antagonist. Separate dosing with an antacid by at least 2 hours.

Avoid co-administration with proton pump inhibitors. Due to the long-lasting effect of proton pump inhibitors, separation of doses may not eliminate the interaction with CALQUENCE.

SPECIFIC POPULATIONS

Based on findings in animals, CALQUENCE may cause fetal harm and dystocia when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. Advise pregnant women of the potential risk to a fetus.

Pregnancy testing is recommended for females of reproductive potential prior to initiating CALQUENCE therapy. Advise female patients of reproductive potential to use effective contraception during treatment with CALQUENCE and for at least 1 week following the last dose of CALQUENCE.

It is not known if CALQUENCE is present in human milk. Advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose.

Avoid administration of CALQUENCE in patients with severe hepatic impairment. Dose modifications are not required for patients with mild or moderate hepatic impairment.

Please see full Prescribing Information including Patient Information.

CALAVI
CALAVI is a large, randomised, open-label, multicentre, global, two-part trial evaluating the efficacy and safety of Calquence with BSC versus BSC alone in patients hospitalised with respiratory complications of COVID-19. Part one is randomised (2:1) and evaluates the addition of Calquence to current BSC in patients who are hospitalised but not on assisted ventilation and not in the ICU. Part two evaluates the addition of Calquence to BSC in a cohort of patients in the ICU with more severe respiratory complications. The trial is being conducted in multiple sites around the world. The primary endpoint measures the use of assisted ventilation or death.

COVID-19
Coronavirus disease 2019 (COVID-19) is a new pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Most COVID-19 cases (~80%) are mild respiratory illnesses. However, some require hospitalisation, mostly due to pneumonia, and can progress quickly to severe acute lung injury and acute respiratory distress syndrome (ARDS), which is associated with high mortality.1,2,3,4 A viral-induced cytokine storm or “hyperimmune response” is hypothesised to be a major pathogenic mechanism of ARDS in these patients through modulation of pulmonary macrophages and dendritic cells and/or neutrophils.5,6,7,8

Calquence
Calquence is a next-generation, selective inhibitor of BTK. Calquence binds covalently to BTK, thereby inhibiting its activity.9,10,11,12 In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.13

Calquence (acalabrutinib) is approved for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) in the US and a few other countries with an active global filing programme. In addition, Calquence is indicated for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy in the US and several other countries.

BTK Inhibition
In lung macrophages, BTK is a key regulator of the production of multiple cytokines and chemokines including TNFa, IL-6, IL-10, and MCP-1, among others.  BTK inhibition reduces the production of these cytokines and is, therefore, a promising strategy to reduce the respiratory complications of COVID-19.13

There is evidence that dysregulated BTK-dependent macrophage signalling may be central to the exaggerated inflammatory responses to SARS-COV-2 and play a role in COVID-19 pneumonia and ARDS. 4,5,6,7 In macrophages, TLR3, TLR7 and TLR8 can recognize single strand RNA from viruses such as SARS-COV-2 and initiate signalling through BTK-dependent activation of NF-kB and IRF3, triggering the production of multiple inflammatory cytokines and chemokines. 5,6,7,8 In support of the role of BTK inhibition, therapeutic inhibition of BTK in patients with lymphoid malignancies results in decreased proinflammatory cytokines and chemokines. Similar findings have been observed in mouse influenza models, where BTK inhibition also decreased these inflammatory mediators and rescued mice from lethal acute lung injury.

AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow the Company on Twitter @AstraZenecaUS.

References

1. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497-506.

2. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020 Feb 24. doi: 10.1001/jama.2020.2648. [Epub ahead of print]

3. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395:1054-62.

4. Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host Microbe. 2016; 19:181-93.

5. Huang KJ, Su IJ, Theron M, et al. An interferon-gamma-related cytokine storm in SARS patients. J Med Virol. 2005; 75:185-94.

6. Wong CK, Lam CW, Wu AK, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 2004; 136:95-103.

7. Yoshikawa T, Hill T, Li K, et al. Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells. J Virol. 2009; 83:3039-48.

8. Herold S, Becker C, Ridge KM, et al.  Influenza virus-induced lung injury: pathogenesis and implications for treatment.  Eur Respir J. 2015; 45:1463-78.

9. Calquence (acalabrutinib) [prescribing information]. Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2019.

10. Wu J, Zhang M & Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9(21).

11. Khan Y & O’Brien S. Acalabrutinib and its use in treatment of chronic lymphocytic leukemia. Future Oncol. 2018;15(6).

12. Byrd JC, et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016; 374:323-332.

13. Buggy JJElias L. Bruton tyrosine kinase (BTK) and its role in B-cell malignancy.  International Reviews of Immunology. 2012 Apr;31(2):119-32. doi: 10.3109/08830185.2012.664797.2012


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