Acalabrutinib COVID-19 Trial Launching

Acalabrutinib (Calquence), a BTK inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), is being explored in the CALAVI trial as a treatment for cytokine storm in patients with COVID-19.¹

Cytokine storm, a type of severe immune overreaction that has presented in severely ill patients with COVID-19, can cause life-threatening respiratory complications. AstraZeneca, the developer of acalabrutinib, explained in a press release that clinical data have shown the BTK pathway has a role in the production of inflammatory cytokines, and early clinical results with acalabrutinib suggest that reducing inflammation through BTK inhibition alleviates the severity of respiratory distress caused by COVID-19.

“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,”

Louis M. Staudt, MD, PhD, senior investigator on the study and chief of the Lymphoid Malignancies Branch at the National Cancer Institute, said in the press release.

Accrual for the CALAVI study is anticipated to commence shortly in the United States and

Europe. The principal investigator is Wyndham H. Wilson, MD, PhD, of the National Cancer Institute.

The FDA approved acalabrutinib in November 2019 for the treatment of patients with CLL or small lymphocytic lymphoma, based on data from the ELEVATE-TN trial and the ASCEND trial. Results from the phase III ELEVATE-TN trial presented at the 2019 ASH Annual Meeting showed that acalabrutinib as a single agent or in combination with obinutuzumab (Gazyva) led to a statistically significant improvement in progression-free survival (PFS) compared with obinutuzumab plus chlorambucil in treatment-naïve patients with CLL.²

At a median follow-up of 28.3 months, the combination of the BTK inhibitor with obinutuzumab led to a 90% reduction in the risk of disease progression or death compared with obinutuzumab/chlorambucil (HR, 0.10; 95% CI, 0.06-0.17; P <.0001). When used as monotherapy, acalabrutinib also showed a statistically significant benefit in PFS (HR, 0.20; 95% CI, 0.13-0.30; P <.0001).

In the randomized, multicenter, open-label, phase III ELEVATE-TN (ACE-CL-007) trial, investigators evaluated the safety and efficacy of acalabrutinib alone or in combination with obinutuzumab versus chlorambucil/obinutuzumab in 535 treatment-naïve patients with CLL. Patients were randomized 1:1:1 into 3 arms: chlorambucil plus obinutuzumab (n = 177); 100 mg of acalabrutinib twice daily in combination with obinutuzumab until disease progression or unacceptable toxicity (n = 179); or single-agent acalabrutinib at 100 mg twice daily until disease progression or unacceptable toxicity (n = 179). Patients were stratified by 17p deletion status, ECOG performance status of 0 to 1 or 2, and geographic region.

Crossover from the obinutuzumab/chlorambucil arm was permitted after independent review committee (IRC)-confirmed disease progression; therefore, these patients were not included in the PFS data that were presented during the 2019 ASH Annual Meeting.

An interim analysis was planned based on events, which was after the occurrence of ~111 IRC-assessed PFS in the combination arms, or after 24 months if the required number of events was not met by this time.

Results by IRC assessment showed that the median PFS was not reached with either acalabrutinib arm, compared with 22.6 months (95% CI, 20.2-27.6) with chlorambucil/obinutuzumab. The 2-year PFS rates were 93%, 87%, and 47% for acalabrutinib/obinutuzumab, single-agent acalabrutinib, and chemoimmunotherapy, respectively.

Although the trial was not powered or designed to compare the PFS outcomes between the 2 acalabrutinib arms, Sharman noted that an exploratory posthoc analysis showed that acalabrutinib plus obinutuzumab was superior to acalabrutinib alone (HR, 0.49; 95% CI, 0.26-0.95).

The IRC-assessed ORR (objective response rate)was 93.9% (95% CI, 89.3-96.5) with acalabrutinib/obinutuzumab and was 78.5% (95% CI, 71.6-89.9) with chemoimmunotherapy (P <.0001), a difference that was found to be statistically significant. The acalabrutinib combination ORR comprised a 13% complete response (CR) rate and an 81% partial response (PR) rate; 2% of patients achieved stable disease (SD).

In the single-agent acalabrutinib arm, the ORR was 85.5% (95% CI, 79.6-89.9) with a 1% CR rate, an 85% PR rate, and a 5% SD rate; compared with the chlorambucil/obinutuzumab ORR, this difference was not found to be statistically significant, according to Sharman. The obinutuzumab/chlorambucil arm consisted of a 5% CR rate, 74% PR rate, and a 9% SD rate.

The rates of grade ≥3 AEs were 70.2%, 49.7%, and 69.8%, respectively. Twelve grade 5 AEs were observed in the chemoimmunotherapy arm, 7 in the acalabrutinib monotherapy arm, and 5 in the acalabrutinib combination arm; these were pulled from the entire treatment-emergent and non—treatment-emergent period.

The most common all-grade adverse events (AEs; ≥15%) in the acalabrutinib/obinutuzumab and single-agent acalabrutinib arms were headache (39.9% vs 36.9%, respectively), diarrhea (38.8% vs 34.6%), neutropenia (31.5% vs 10.6%), fatigue (28.1% vs 18.4%), contusion (23.6% vs 15.1%), arthralgia (21.9% vs 15.6%), cough (21.9% vs 18.4%), upper respiratory tract infection (21.3 vs 18.4%), nausea (20.2% vs 22.3%), and dizziness (18.0% vs 11.7%). Grade ≥3 neutropenia was highest with obinutuzumab/chlorambucil (41.4%) versus acalabrutinib/obinutuzumab (29.8%) and acalabrutinib alone (9.5%).

On October 31, 2017, the FDA granted an accelerated approval to acalabrutinib as a treatment for adult patients with MCL following at least 1 prior therapy. The approval was based on data from the ACE-LY-004 study (NCT02213926), long-term data from which were presented at the 2018 American Society of Hematology meeting.³

At a median follow-up of 26 months (range 0.3-35.1), 49 of 124 patients (40%) remain on treatment. The investigator-assessed ORR was 81% (95% CI, 73-87), with 43% (95% CI, 34-52) of patients achieving a complete response (CR). The median overall survival (OS) was not reached (NR).

An analysis of minimum residual disease (MRD) using next generation sequencing (10-6) in 29 patients demonstrated that 8 achieved undetectable MRD in at least 1 blood sample tested (28%). All patients with MRD negativity had CRs.

The single-arm study enrolled 124 patients with relapsed/refractory MCL. Patients received oral acalabrutinib at 100 mg twice-daily in 28-day cycles until disease progression or unacceptable toxicity. Most patients were intermediate risk by simplified MCL International Prognostic Index scores (44%) and 8% had bulky lymph nodes (≥10 cm). Seventy-two percent had extranodal disease.

At the long-term follow-up, 40% or patients remain on acalabrutinib and 61% remain on study. Of the 60% who discontinued acalabrutinib, 44% did so because of disease progression, 8% due to an AE, and 5% initiated subsequent anticancer therapy. The median relative dose intensity (ratio of actual to planned cumulative dose during drug exposure period) was 99%.

The 81% ORR at 26 months was identical to the 15-month ORR, and some patients who initially had a partial response converted to a CR at 26 months, noted Wang. The CR rate increased from 40% at 15 months to 43% at 26 months. The ORRs were consistent across prespecified subgroups based on tumor bulk, presence of refractory disease, and number/type of prior treatment.

The median duration of response (DOR) was 26.0 months (95% CI, 17.5-NR), and the 24-month DOR rate was 52.4% (95% CI, 41.5-62.2). The median progression-free survival (PFS) was 20.0 months (95% CI 16.5-27.7), and the 24-month PFS rate was 49% (95% CI, 40-58), The estimated 24-month OS rate was 72% (95% CI, 64-80).

The most frequent AEs any-grade AEs included headache (38%), diarrhea (36%), fatigue (28%), cough (22%) and myalgia (21%), most of which were grade 1/2. Grade 3/4 AEs in ≥5% included anemia (11%) and neutropenia (11%).

References

1. AstraZeneca initiates CALAVI clinical trial with Calquence against COVID-19. Published April 14, 2020. https://bit.ly/2Vc3lA1. Accessed April 14, 2020.
2. Sharman JP, Banerji V, Fogliatto LM, et al. Phase 3 study of acalabrutinib combined with obinutuzumab or alone versus obinutuzumab plus chlorambucil in patients with treatment-naïve chronic lymphocytic leukemia: results from ELEVATE-TN. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, Florida. Abstract 31. bit.ly/33ST9NS.
3. Wang M, Rule S, Zinzani PL, et al. Long-term follow-up of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego. Abstract 2876.

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The CALAVI trial is a large, multicenter, international study comprising a 2-part design. In part 1 of the trial patients hospitalized with respiratory complications of COVID-19 who are not on assisted ventilation and not in the ICU will be randomized in a 2:1 ratio to acalabrutinib plus best supportive care (BSC) versus BSC alone. The randomization will be the same in Part 2, but this segment will comprise a cohort of patients in the ICU with more severe respiratory complications. The primary outcome measures are mortality and the need for assisted ventilation.