Novel JAK1 Inhibitor Safely Induces Preliminary Antitumor Activity in R/R PTCL

The investigational selective JAK1 inhibitor, DZD4205, led to anti-tumor activity when given as treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL), according to results from the phase 1/2 JACKPOT8 clinical trial (NCT04105010) published in Blood.

Results were previously reported during the 2020 American Society of Hematology (ASH) Virtual Annual Meeting by Won-Seog Kim of Samsung Medical Center who at the time stated, “DZD4205 demonstrated promising anti-tumor activity, favorable pharmacokinetic properties, as well as an acceptable and comparable safety profile in patients with relapsed/refractory PTCL.”

The historical 5-year overall survival rate for patients with relapsed/refractory PTCL is below 30%. With treatments that are approved by the FDA for this patient population, patients have been shown to achieve an objective response rate (ORR) of < 30% and median a progression-free survival of just 4 months, representing a poor prognosis for these patients.

Based on early research suggesting that targeting the JAK-STAT may interfere with PTCL pathogenesis, the JACKPOT8 trial was conducted in 36 patients with the goal of determining the efficacy, safety/tolerability, and pharmacokinetics of DZD4205 in patients with relapsed/refractory disease.

Patients were treated in dose-escalation cohorts and an extension cohort. In cohort 1, patients received 150 mg of DZD4205 once daily (QD). The dosage of DZD4205 was increased to 250 mg QD in cohort 2, and in cohort 3, patients were treated at a selected dose level. Therapy was administered to patients continuously for a period of 21 days or until disease progression or intolerance to the drug. The study was designed to determine the recommended phase 2 dose of DZD4205.

Preliminary results on the primary end point of safety and tolerability showed a toxicity profile that was similar to that observed with other FDA-approved therapies. Overall, the toxicities were tolerable in patients. Grade 3 or higher treatment-emergent adverse events occurred in > 10% of patients, and the most common were thrombocytopenia, neutropenia, and infections. Most of the TEAEs observed in the study were manageable or reversible with or without adjusting the dose level of DZD4205.

Regarding the PK of the novel JAK1inhibitor, a co secondary end point explored in JACKPOT8, Kim stated “ DZD4205 shows a desirable PK profile in this population with a relatively long half-life and a low fluctuation at the study stage. Systemic exposure was appropriately dose proportional at the doses investigated.”

Anti-tumor activity was assessed in 29 patients by CT per investigators and by PET scan according to Lugano criteria. The ORR observed was 42%, which included complete responses (CRs) in 21% of patients. Another 37% of the study population was treated for more than 3 months and achieved 40% of these patients achieved a CR after receiving DZD4205. Notably, the PTCL subtypes that responding to therapy included AITL which made up 50.0% of the population, PTCL-NOS (33.3%), ALCL ALK-negative (5.6%), and NKTCL (8.3%).

Patients enrolled in JACKPOT8 has a median age of 63.5 years (range, 29-79) and were predominantly male. Nine patients were female. Overall, 52.8% of patients had an ECOG performance status of 0 while the remaining 47.2% had an ECOG performance status of 1. Most patients enrolled had 3 or more prior line of therapy. The most common prior therapy was chemotherapy (100%), followed by histone deacetylase inhibitor (19.4%), and CD30 targeted therapy (5.6%). Twenty-five percent of patients had bone marrow involved at baseline screening and 13.9% underwent stem cell transplantation.

At the time these data were reported, patients were still being enrolled in the phase 2 single-arm, open-label portion of the study.

_References:

_{Kim WS, Yoon DH, Koh Y, et al. A phase I/II Study (JACKPOT8) of DZD4205, a selective JAK1 inhibitor, in refractory or relapsed peripheral t- cell lymphoma. Blood. 2020;136(Supp 1); 19–20. doi: 10.1182/blood-2020-134650}