16 August 2019 - - The US Food and Drug Administration has granted Breakthrough Therapy Designation for Calquence (acalabrutinib) as a monotherapy treatment for adult patients with chronic lymphocytic leukemia, one of the most common types of leukemia in adults, British-Swedish drugmaker AstraZeneca said.

The FDA granted the BTD based on positive results from the interim analyses of the ELEVATE-TN and ASCENDPhase III clinical trials.

Together the trials showed that Calquence alone, or in combination with obinutuzumab, significantly increased the time patients lived without disease progression or death, with safety and tolerability that was consistent with its established profile.

This is the 10th BTD that AstraZeneca has received from the FDA since 2014.

An FDA BTD is designed to accelerate the development and regulatory review of new medicines that are intended to treat a serious condition and that have shown encouraging early clinical results which may demonstrate substantial improvement on a clinically-significant endpoint over currently-available medicines.

Calquence is currently approved for the treatment of adults with relapsed or refractory mantle cell lymphoma in the US, Brazil, Qatar, the United Arab Emirates, Mexico, Argentina and recently Singapore and is being developed for the treatment of CLL and other blood cancers.

In the US, 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.

The positive results from both the ELEVATE-TN and ASCEND trials will serve as the foundation for regulatory submissions later this year.

Serious hemorrhagic events, including fatal events, have occurred in the combined safety database of 612 patients with hematologic malignancies treated with Calquence monotherapy.

Grade 3 or higher bleeding events, including gastrointestinal, intracranial, and epistaxis, have been reported in 2% of patients.

Overall, bleeding events, including bruising and petechiae of any grade, occurred in approximately 50% of patients with hematological malignancies.

ELEVATE-TN (ACE-CL-007) is a randomized, multicenter, open-label Phase III trial evaluating the safety and efficacy of Calquence alone or in combination with obinutuzumab vs. chlorambucil in combination with obinutuzumab in previously-untreated patients with CLL.

In the trial, 535 patients were randomized (1: 1: 1) into three arms. Patients in the first arm received chlorambucil in combination with obinutuzumab.

Patients in the second arm received Calquence (100mg twice daily until disease progression or unacceptable toxicity) in combination with obinutuzumab. Patients in the third arm received Calquence monotherapy (100mg twice daily until disease progression or unacceptable toxicity).

The primary endpoint is progression-free survival in the Calquence and obinutuzumab arm compared to the chlorambucil and obinutuzumab arm, assessed by an independent review committee, and a key secondary endpoint is IRC-assessed PFS in the Calquence monotherapy arm compared to the chlorambucil and obinutuzumab arm.

Other secondary endpoints include objective response rate, time to next treatment and overall survival.

ASCEND (ACE-CL-309) is a global, randomized, multicenter, open-label Phase III trial evaluating the efficacy of Calquence in previously-treated patients with CLL. In the trial, 310 patients were randomized into two arms.

Patients in the first arm received Calquence monotherapy (100mg twice daily until disease progression or unacceptable toxicity).

Patients in the second arm received investigator's choice of either rituximab in combination with idelalisib or rituximab in combination with bendamustine.

The primary endpoint is PFS assessed by an IRC, and key secondary endpoints include investigator-assessed PFS, IRC- and investigator-assessed overall response rate and duration of response, as well as overall survival, patient reported outcomes and time to next treatment.

Calquence (acalabrutinib) was granted accelerated approval by the US Food and Drug Administration in October 2017 for the treatment of adult patients with MCL who have received at least one prior therapy. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Calquence is an inhibitor of Bruton tyrosine kinase. Calquence binds covalently to BTK, thereby inhibiting its activity. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.

As part of an extensive clinical development programme, AstraZeneca and Acerta Pharma are currently evaluating Calquence in 26 company-sponsored clinical trials.

Calquence is being developed for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenstrom macroglobulinemia, follicular lymphoma, and multiple myeloma and other hematologic malignancies.

Several Phase III clinical trials are ongoing, including ASCEND, ELEVATE-TN, ELEVATE-RR (ACE-CL-006) evaluating acalabrutinib vs. ibrutinib in patients with previously treated high-risk CLL, and ACE-CL-311 evaluating acalabrutinib in combination with venetoclax and with/without obinutuzumab in patients with previously-untreated CLL without 17p deletion or TP53 mutation.