A Phase Ib/II Study of Anti-CD30 Chimeric Antigen Receptor T Cells for Relapsed/Refractory CD30+ Lymphomas

Introduction Treatment with chimeric antigen receptor modified T cells targeting CD30 (CD30.CAR-Ts) without lymphodepletion was found to be safe with preliminary efficacy in patients (pts) with relapsed/refractory (r/r) CD30+ lymphomas (Ramos et al., JCI 2017). We report the results of a phase 1b/2 trial of CD30.CAR-Ts infused after lymphodepletion in pts with r/r CD30+ Hodgkin (HL) and Non-Hodgkin lymphoma (NHL). Objectives The primary objective of the phase Ib portion of the study was to determine the phase 2 dose of CD30.CAR-Ts using a standard 3+3 design. Methods Pts ≥ 18 years with r/r CD30+ HL or NHL having failed ≥2 prior therapies were eligible. Two dose levels were tested: 1 × 10 8 CAR-Ts/m 2 (DL1) and 2 × 10 8 CAR-Ts/m 2 (DL2). The first 8 pts (including the 3 pts on DL1) received bendamustine (benda) 90 mg/m 2 × 2 days and the remaining 16 pts received benda 70 mg/m 2 and fludarabine (flu) 30 mg/m 2 × 3 days. Results At the time of data cut off (10/1/2018), 24 pts had been treated and undergone response assessment. The median age was 35.5 years (range: 23-70). 22 pts had HL, 1 had enteropathy associated T cell lymphoma and 1 had Sezary syndrome. Pts had undergone a median of 7.5 prior lines of therapy (range: 3-17). 23 pts had received prior brentuximab vedotin. 15 pts had prior autologous stem cell transplant (SCT) and 7 had prior allogeneic SCT. As there were no dose limiting toxicities, DL2 was administered as the phase 2 dose. 3 pts developed grade 1 cytokine release syndrome (CRS) and 1 pt had grade 2 CRS which responded to tocilizumab. 19 out of 24 pts had evidence of disease prior to lymphodepletion and were included in efficacy analysis. 10 pts had a CR at the 6 week assessment (53%, all in benda/flu cohort), 2 had partial response (11%), 2 had stable disease (11%), and 5 had progressive disease (26%, including all 3 pts treated at DL1). At median follow up of 180 days, the median PFS was 164 days. The median PFS for the 14 evaluable pts who received benda/flu at DL2 was 389 days. Using peripheral blood PCR, CD30.CAR-Ts peaked at wk 2 post infusion, with increasing CAR-Ts in pts receiving a higher dose or more robust lymphodepletion (3.4 × 10 3 ± 2.9 × 10 3 copies/ug of DNA for DL1-beda vs. 61 × 10 3 ± 41 × 10 3 for DL2-benda vs. 49 × 10 3 ± 16 × 10 3 for benda/flu). These differences were confirmed by flow cytometry (CD3 + CAR + cells = 13%±9% for DL1-benda vs 21%±10% for DL2-benda vs 35%±8% for benda/flu). There was also improved persistence at wk4 for higher dose and with addition of flu to lymphodepletion (0.06 × 10 3 ± 0.01 × 10 3 vs. 0.44 × 10 3 ± 0.41 × 10 3 vs. 25 × 10 3 ± 11 × 10 3 /ug of DNA at wk 4 for DL1-benda, DL2-benda, and benda/flu, respectively). Conclusion CD30.CAR-Ts administered with lymphodepletion with benda/flu are safe and have promising anti-tumor activity for pts with r/r CD30+ lymphomas. A higher dose of CD30.CAR-Ts and the addition of flu to lymphodepletion increased T cell expansion and persistence and translated to improved efficacy.