CL-001 FIH Study: New BTK Inhibitor Effective in Early Stage Study of Relapsed/Refractory CLL/SLL

di Mary Mosley

A second-generation BTK inhibitor, acalabrutinib (ACP-196), has demonstrated an overall response rate (ORR) of 95% along with a durable remission and favorable safety profile in patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The results of the phase 1/2 study were reported by John C. Byrd, MD, The Ohio State University, Columbus, Ohio, USA [Byrd JC et al. N Engl J Med 2015, and lend further support to the benefit of targeting the Bruton tyrosine kinase (Btk).

Effectively targeting BTK represents a major advance in treating CLL and other B-cell lymphoproliferative disorders. More selective than the first-generation drug ibrutinib, acalabrutinib is a potent, irreversible drug that does not inhibit ITK or RLK, thereby not inhibiting direct cytotoxicity, and it has demonstrated in vivo antitumor activity.

This first-in-human study of safety of acalabrutinib also examined the maximal tolerated dose, pharmacokinetics and pharmacodynamics, and tumor response and progression-free survival. A total of 61 patients were randomized to one of four dose cohorts: 100 mg (n = 9), 175 mg (n = 8), 250 mg (n = 7), and 400 mg (n = 6). The phase 3 expansion study examined 100 mg twice daily in 31 patients. The treatment cycle was 28 days. The pharmacokinetic and pharmacodynamic data demonstrated that the twice daily dose provided complete and continuous BTK coverage.

Although patients were naïve to BTK inhibitors, they had undergone a median of three prior therapies (range, 1-13) and 52% had undergone ≥3 prior therapies. PI3K-delta or BCL-2 inhibitors and bone marrow transplant were allowed. Many patients were at high risk, with 31% with the 17p deletion, 29% with the 11q deletion, and 75% with unmutated immunoglobulin heavy-chain variable genes at baseline. Sixty-seven percent had stage III/IV disease, 46% had bulky lymph nodes ≥5 cm, and 72% with cytopenia. Their median age was 62 years (range, 44-84) and most (85%) were men.

After the median follow-up of 14.3 months, 85% of patients had a partial response (PR) and 10% had a PR plus lymphocytosis (Table 1). The patients with the 17p deletion had similarly good responses, with an ORR of 100%, PR of 89%, and PR plus lymphocytosis of 11%. The responses were durable, with no patients having progressive disease and 3 patients with stable disease.

Acalabrutinib elicits responses quickly, with a fast onset of a PR and a fast decline in PR plus lymphocytosis (Figure 1). The faster resolution of lymphocytosis with acalabrutinib was most notable, according to Dr. Byrd, with a peak at a median of 3 weeks and resolution by a median of 19 weeks (range, 1-58). There was resolution in 81% of the 61% of patients with treatment-related lymphocytosis (defined as ≥50% increase from baseline and above absolute lymphocyte count [ALC] of 5 K/µL). Lymphadenopathy was measured by computed tomography.

The safety profile of acalabrutinib is promising, with no episodes of atrial fibrillation or major bleeding. Most adverse events (AEs) were of grade 1 or 2 severity and headache and bruising were the most common treatment-related AE. Serious AEs were limited to febrile neutropenia in 1 patient, pneumonia in 6 patients, autoimmune hemolytic anemia in 2 patients, and pyrexia in 2 patients.

Eight of the 61 patients discontinued treatment. Two stopped treatment because of the decision of the investigator or patient, 1 patient died from pneumonia, and 1 patient had CLL progression. Other causes of stopping treatment were active automimmune hemolytic anemia requiring additional therapy in 1 patient and one case each of diarrhea, gastritis, and dyspnea.

Overall, this study demonstrated that the second-generation, selective BTK inhibitor acalabrutinib has favorable biochemical and pharmacokinetic properties, a positive safety profile, and was associated with less significant or persistent early-onset, treatment-related lymphocytosis compared with other inhibitors of B-cell receptors. Further, there was a high response rate and durable remission, regardless of del(17p) status, and no cases of Richter’s transformation were observed.

A phase 3 study of acalabrutinib in high-risk, pretreated patients with CLL is now underway (NCT02477696).

Source: ASH 2015,
abs 831

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