Cpi-818, an Oral Interleukin-2-Inducible T-Cell Kinase Inhibitor, Is Well-Tolerated and Active in Patients with T-Cell Lymphoma

Background:

Interleukin-2-Inducible T-Cell Kinase (ITK) is a Tec‑family, non‑receptor tyrosine kinase expressed in T-cells that plays a key role in T-cell receptor (TCR) signaling, which is required for development and differentiation of T-cells. In T-cell lymphoproliferative disorders, expression of the TCR and its downstream signaling components, including ITK, are maintained which suggests malignant T cells exploit this growth and survival pathway to their advantage. Antigen‑presenting cells, abundant in the lymphoma microenvironment, also may provide antigen to drive TCR signaling through ITK. CPI-818 is a first-in-class, irreversible ITK inhibitor with selectivity for ITK. In preclinical studies, CPI-818 blocks TCR signaling in vitro and is efficacious in murine models and canines with T-cell lymphomas. We report results from the dose escalation portion of an ongoing phase 1/1b trial of CPI-818 in patients with relapsed/refractory T-cell lymphoma (CPI-818-001 study, NCT03952078). The trial is being conducted at sites in the United States, Australia, and South Korea.

Methods:

In dose-escalation, cohorts (3+3 design) enrolled patients with cutaneous and peripheral T-cell lymphoma who have progressed on, refractory to, relapsed, or intolerant to at least 2 standard therapies; age ≥ 18 years; ECOG status 0-1; and adequate organ function. CPI-818 was administered in ascending dose levels (100, 200, 400, 600mg BID) continuously for up to sixteen 21-day cycles, until progression or unacceptable toxicity. In dose expansion, PTCL-NOS and CTCL patients are receiving CPI-818 at a dose of 600 mg BID.

The primary objectives of the study are to evaluate the safety and to establish the maximum tolerated dose (MTD) or the maximum administered dose of CPI-818. Safety events will be assessed according to the NCI-CTCAEv5. Secondary objectives include evaluating pharmacokinetics and efficacy as assessed by the investigator using standard response criteria at the end of every 3 cycles. ITK occupancy in peripheral blood T cells and tumor tissue as well as biomarkers associated with anti-tumor activity in tumor and blood samples are being evaluated.

Results:

In dose-escalation, sixteen patients were enrolled in four cohorts: 100 mg BID (n=4), 200 mg BID (n=3), 400 mg BID (n=5), and 600 mg BID (n=4). No dose-limiting toxicities were observed in any of these cohorts and the MTD was not reached. Treatment related adverse events (TRAEs) were reported in 9 (47.4%) patients and were all Grade 1-2 in severity. The most common (>1 patient) were fatigue (15.8%), nausea (10.5%), and rash (10.5%) and no infections were reported. By flow cytometry, no consistent changes in circulating non-malignant or total T cell number or phenotype were observed. Pharmacodynamic analysis revealed ITK engagement by CPI-818 in all cohorts when CPI-818 is dosed BID. With increasing dose, the trough ITK occupancy in both blood and tissue increased. At doses of 200 mg and greater, trough occupancies were >75%. Near complete ITK inhibition (98%) was achieved at 600 mg BID and therefore, this dose was selected as the expansion cohort dose and higher doses were not explored. Reduction in serum cytokines including IL2 (six of eight patients), IFNg (eight of eight patients), and TNFa (eight of eight patients) was observed 24hr post-dose in patients treated with doses of 400 and 600mg, but not at lower doses. In dose escalation, a total of four PTCL patients were enrolled at doses of 200 mg BID or greater. A confirmed complete response was achieved in one PTCL-NOS patient in the 200mg BID cohort. Among 7 CTCL patients enrolled, a Nodal CR, improved mSWAT and slowing of Sézary cell expansion were seen (Figure 1). Given the safety profile, the PK/PD findings, and the early signs of efficacy, PTCL-NOS and CTCL cohorts were expanded at 600mg BID. To date, two patients with PTCL-NOS and one patient with CTCL have been recently enrolled in expansion cohorts.

Conclusion:

The dose-escalation part of the CPI-818-001 trial demonstrated that the 100, 200, 400 and 600 mg BID doses are well tolerated. Clinical activity was observed in both PTCL-NOS and CTCL. Reduction of serum levels of canonical T cell cytokines is consistent with on-mechanism drug inhibition of inflammatory T cell pathways. Disease specific expansion cohorts for PTCL-NOS and CTCL are enrolling patients at a dose of 600 mg BID.