Leukemias, lymphomas, and other hematologic cancers:

Indications for: CALQUENCE

Mantle cell lymphoma (MCL) in adults who have received at least one prior therapy. Chronic lymphocytic leukemia (CLL). Small lymphocytic lymphoma (SLL).

Clinical Trials:

Mantle Cell Lymphoma 

The efficacy of Calquence was based upon Trial LY-004 titled “An Open-label, Phase 2 Study of ACP-196 in Subjects with Mantle Cell Lymphoma” (NCT02213926). Trial LY-004 enrolled a total of 124 patients with MCL who had received at least one prior therapy.

At baseline, 93% of patients had an ECOG performance status of 0 or 1. The median time since diagnosis was 46.3 months and the median number of prior treatments was 2 (range 1-5), including 18% with prior stem cell transplant. The most common prior regimens were CHOP-based (52%) and ARA-C (34%). At baseline, 37% of patients had at least one tumor with a longest diameter ≥ 5 cm, 73% had extra nodal involvement including 51% with bone marrow involvement. 

Calquence was administered orally at 100 mg approximately every 12 hours until disease progression or unacceptable toxicity. The median dose intensity was 98.5%. The major efficacy outcome of Trial LY004 was overall response rate and the median follow-up was 15.2 months.

Results showed that patients treated with Calquence achieved an ORR of 81% (95% CI, 73-87) with 40% of those having complete response and 41% having partial response. The median time to best response was 1.9 months. 

Chronic Lymphocytic Leukemia 

The efficacy of Calquence in patients with CLL was demonstrated in two randomized, controlled trials. The indication for acalabrutinib includes patients with SLL because it is the same disease.

ELEVATE-TN: 

The efficacy of Calquence was evaluated in the ELEVATE-TN trial, a randomized, multicenter, open-label, actively controlled, 3 arm trial of Calquence in combination with obinutuzumab, Calquence monotherapy, and obinutuzumab in combination with chlorambucil in 535 patients with previously untreated chronic lymphocytic leukemia (NCT02475681).

Patients were randomly assigned in a 1:1:1 ratio into 3 arms to receive: 

  • Calquence plus obinutuzumab (Calquence+G): Calquence 100 mg was administered approximately every 12 hours starting on Cycle 1 Day 1 until disease progression or unacceptable toxicity. Obinutuzumab was administered starting on Cycle 2 Day 1 for a maximum of 6 treatment cycles. Obinutuzumab 1000 mg was administered on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 2 followed by 1000 mg on Day 1 of Cycles 3 up to 7. Each cycle was 28 days.
  • Calquence monotherapy: Calquence 100 mg was administered approximately every 12 hours until disease progression or unacceptable toxicity.
  • Obinutuzumab plus chlorambucil (GClb): Obinutuzumab and chlorambucil were administered for a maximum of 6 treatment cycles. Obinutuzumab 1000 mg was administered intravenously on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 8 and 15 of Cycle 1 followed by 1000 mg on Day 1 of Cycles 2 to 6. Chlorambucil 0.5 mg/kg was administered orally on Days 1 and 15 of Cycles 1 to 6. Each cycle was 28 days.

Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). The median duration of follow-up was 28.3 months (range: 0.0-40.8 months).

Results showed that patients who received Calquence had a longer PFS compared with those who received obinutuzumab plus chlorambucil. In the Calquence combination arm, risk of disease progression or death was reduced by 90% (hazard ratio [HR] 0.10; 95% CI, 0.06-0.17, P <.0001) and in the monotherapy arm it was reduced by 80% (HR 0.20; 95% CI, 0.13-0.30, P <.0001). 

With a median follow-up of 28.3 months, median overall survival was not reached in any arm, with fewer than 10% of patients experiencing an event.

ASCEND: 

The efficacy of Calquence in patients with relapsed or refractory CLL was based upon a multicenter, randomized, open-label trial (ASCEND; NCT02970318). The trial enrolled 310 patients with relapsed or refractory CLL after at least 1 prior systemic therapy.

Patients were randomly assigned in a 1:1 ratio to receive either: 

  • Calquence 100 mg approximately every 12 hours until disease progression or unacceptable toxicity, or
  • Investigator’s choice:
    • Idelalisib plus a rituximab product (IR): Idelalisib 150 mg orally approximately every 12 hours until disease progression or unacceptable toxicity, in combination with 8 infusions of a rituximab product (375 mg/m2 intravenously on Day 1 of Cycle 1, followed by 500 mg/m2 every 2 weeks for 4 doses and then every 4 weeks for 3 doses), with a 28-day cycle length.
    • Bendamustine plus a rituximab product (BR): Bendamustine 70 mg/m2 intravenously (Day 1 and 2 of each 28-day cycle), in combination with a rituximab product (375 mg/m2 intravenously on Day 1 of Cycle 1, then 500 mg/m2 on Day 1 of subsequent cycles), for up to 6 cycles.

In the Calquence arm, the median treatment duration was 15.7 months, with 94% of patients treated for at least 6 months and 86% of patients treated for at least 1 year. In the investigator’s choice arm, the median treatment duration was 8.4 months, with 59% of patients treated for at least 6 months and 37% treated for at least 1 year.

Efficacy was based on PFS as assessed by an IRC, with a median follow-up of 16.1 months (range 0.03-22.4 months). In this trial, treatment with Calquence resulted in longer PFS compared with the other standard treatments (HR 0.31; 95% CI, 0.20-0.49; P <.0001). There was no statistically significant difference in overall response rates between the two treatment arms. 

With a median follow up of 16.1 months, median overall survival was not reached in either arm, with fewer than 11% of patients experiencing an event.

Adult Dosage:

Swallow whole with water. 100mg approx. every 12hrs until disease progression or unacceptable toxicity. In combination with obinutuzumab (CLL/SLL): initiate acalabrutinib at Cycle 1 of each 28-day cycle, then initiate obinutuzumab at Cycle 2 for a total of 6 cycles; give acalabrutinib prior to obinutuzumab if given on same day. Concomitant moderate CYP3A inhibitors: 100mg once daily. Concomitant strong CYP3A inducers: avoid; if needed, increase dose to 200mg every 12hrs. Dose modifications: see full labeling.

Children Dosage:

Not established.

CALQUENCE Warnings/Precautions:

Risk of serious hemorrhagic events (monitor); consider the benefit/risk of withholding treatment for 3–7 days pre-and post-surgery. Monitor for infections; consider prophylaxis if at risk for opportunistic infections. Monitor for cytopenias; obtain CBCs regularly. Risk of second primary malignancies (eg, skin cancer or other carcinomas); advise patients to protect from sun exposure. Monitor for atrial fibrillation/flutter; manage appropriately. Severe hepatic impairment: not recommended. Advise females of reproductive potential to use effective contraception during and for ≥1 week after the last dose. Pregnancy: exclude status prior to initiation (potential risk of fetal harm and dystocia). Nursing mothers: not recommended (during and for ≥2 weeks after the last dose).

CALQUENCE Classification:

Bruton tyrosine kinase (BTK) inhibitor.

CALQUENCE Interactions:

Avoid concomitant strong CYP3A inhibitors (eg, itraconazole); if short-term use (eg, anti-infectives for ≤7days), interrupt acalabrutinib therapy. Concomitant moderate CYP3A inhibitors, strong CYP3A inducers (eg, rifampin): see Adults. Increased risk of hemorrhage with concomitant antithrombotics; consider benefit/risk. Antagonized by gastric acid reducing agents (eg, PPI [avoid], H2-receptor antagonist, or antacid); if needed, consider ranitidine, famotidine, or calcium carbonate. Separate dosing by at least 2hrs with antacids. Take acalabrutinib 2hrs before H2-receptor antagonist use.

Adverse Reactions:

Anemia, neutropenia, thrombocytopenia, upper RTI, headache, diarrhea, musculoskeletal pain; hemorrhage, infections, second primary malignancy, atrial fibrillation/flutter.

Metabolism:

Acalabrutinib is predominantly metabolized by CYP3A enzymes, and to a minor extent, by glutathione conjugation and amide hydrolysis, based on in vitro studies. 

Drug Elimination:

The geometric mean (% CV) terminal elimination half-life (t1/2) was 1 (59%) hour for acalabrutinib and 3.5 (24%) hours for ACP-5862.

Following administration of a single 100 mg radiolabeled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine, with <2% of the dose excreted as unchanged acalabrutinib in urine and feces.

Generic Drug Availability:

NO

How Supplied:

Caps—60