Results from the First Phase 1 Clinical Study of DR-01, a Non-Fucosylated Anti-CD94 Targeting Antibody in Patients with Relapsed/Refractory Cytotoxic Lymphomas: Dose Escalation and Optimization

Introduction: DR-01 is a non-fucosylated human IgG antibody targeting CD94, a receptor selectively expressed on cytotoxic terminal effector CD8+T cells, γδT cells, and NK cells, leading to rapid depletion of target cells primarily by antibody-dependent cellular cytotoxicity including fratricide.

DR-01-ONC-001 (NCT05475925) is a Phase 1/2 study of DR-01 in relapsed/refractory (RR) cytotoxic lymphomas (CTL) driven by CD94-expressing cytotoxic cells of origin. In RR disease, these CTLs including hepatosplenic TCL, EATL, MEITL, ENKTL, CD8+ PTCL-NOS, primary cutaneous γδTCL(PCγδTCL), SPTCL, and aggressive CD8+ epidermotropic TCL among others, have no established effective treatment options. Patients with RR CTL have a poor prognosis with shortened survival, often only weeks to months.

Aims: To evaluate the safety and efficacy of DR-01 for the treatment of CTLs and to select doses for dose optimization.

Methods: This is a multi-center, open-label, 2-part study. Part A, dose escalation and extension, included CTL patients who failed at least 2 prior lines of therapy. Patients received IV DR-01 at 1 of 5 dose levels ranging from 0.3 to 10 mg/kg, and 1 of 3 induction dose regimens followed by monthly dosing. Additional CTL patients were enrolled in Part A extension at selected dose-regimens to inform dose optimization. Part B2 expansion will assess efficacy and safety of DR-01 in CTL patients who have failed at least 1 prior therapy at 2 dose levels to optimize dose selection. Study goals include disease response assessments, DR-01 concentrations, and pharmacodynamic/biomarker evaluations.

Results

Safety: 39 patients have been enrolled from July 2022 to May 2024 in the safety cohort including CTL and a separate cohort of LGLL not further described here. There were no dose-limiting toxicities, and the only significant treatment-related adverse event (TRAE) observed was infusion-related reaction (IRR) in 33.3% (N=13) most commonly with first administration and managed with supportive measures. No IRR led to dose reduction or discontinuation other than in the first patient enrolled into the study prior to optimization of IRR prophylaxis. The one TRAE causing a dose modification (missed dose) was grade 1 constipation. TRAEs like headache and fatigue had maximum incidence of 15.4%. One event of pyrexia (grade 2) and 1 event of possible CRS (grade 2), both of which resolved without sequelae, were serious AEs considered possibly related to DR-01. There were no DR-01 related deaths.

Efficacy: Part A enrolled 21 patients with CTL. 74% were resistant/intolerant to the most recent line of therapy and 26% refractory to all prior lines of therapy. 18.5% had a prior autologous or allogeneic hematopoeitic stem cell transplant (HSCT). The observed objective response rate (ORR) was 33.3% (3 complete responses [CR] and 4 partial responses [PR]) in the 21 intention-to-treat patients. Among 16 response evaluable patients at minimally efficacious dose (determined by exposure-response analysis) of 1 mg/kg the ORR was 43.8%. Responses were observed in patients who had no response to any line of prior treatment and were observed across 7 different CTL histologies. Time to response in the 7 subjects who achieved CR or PR ranged from 0.85 to 1.38 months, and duration of response (DoR) ranged from 1.97 to 11.14 months. Two of 3 patients achieving CR proceeded to allogeneic HSCT after 14 cycles (SPTCL) and 7 cycles (ENKTL) on study, and they continue in CR at 4.1 and 6.3 months, respectively, since last dose of DR-01. The third patient achieving CR (PCγδTCL) had previously relapsed post allo-HSCT with ongoing response at 7.89 months.

Dose optimization: Exposure is approximately dose proportional within the dose range tested, and preliminary population pharmacokinetic (PK) modeling predicts a half-life of approximately 2 weeks. No safety/exposure relationship was observed, and the C_min associated with responses was best achieved with dose levels of > 1 mg/kg and with the induction regimen dosing on C1D1, D8 and D15. These data supported initiating enrollment into phase 2, Part B2 at doses up to 10 mg/kg.

Conclusion: DR-01 is safe and tolerable in heavily pretreated patients. An encouraging response rate including 3 durable CRs points to the potential for DR-01 as a viable treatment option for CTL. Study DR-01-ONC-001 is currently enrolling an international cohort of patients with CTL into phase 2, part B2 of the trial.