PS1240 EVEROLIMUS WITH DHAP (DEXAMETHASONE, HIGH‐DOSE ARAC, CISPLATINUM) IN PATIENTS WITH RELAPSED OR REFRACTORY CLASSICAL HODGKIN LYMPHOMA: A RANDOMIZED, PLACEBO‐CONTROLLED PHASE I/II TRIAL (HD‐R3I) (2019)

Background: Induction chemotherapy followed by BEAM high dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplant (PBSC transplant) is standard of care for transplant‐eligible patients with relapsed or refractory classical Hodgkin lymphoma (rrHL). However, approx. 50% of patients relapse and therefore, this strategy must be improved. Aims: As response to induction therapy is predictive of the outcome after HDCT, this trial aimed at improving the response to induction therapy by adding oral everolimus to time‐intensified standard DHAP (Ever‐DHAP). Methods: We included patients with histologically confirmed rrHL aged 18–60 years in this phase I/II trial. Dosage of everolimus was pre‐determined in the phase I part with 10 mg/day in parallel to DHAP for 14 days within each of two cycles. The phase II part started as a randomized controlled trial comparing 50 patients in the everolimus group to 50 patients in a placebo group. The primary endpoint of the phase II part was the CT‐based complete remission (CR‐) rate after two cycles of Ever‐DHAP. This CR‐rate would be expected to be ≥ 40% if adding everolimus was effective. Secondary endpoints of the trial were PET‐based CR‐rate after two cycles of induction, progression‐free and overall survival as well as time to recovery, adverse events, duration of induction therapy, discontinuation rates and rates of successful PBSC collection. The trial was registered at ClinicalTrials.gov with ID NCT01453504. Results: From 7/2014 to 3/2018 we recruited a total of 59 patients in the phase II part. Because of poor recruitment the placebo group was closed in 9/2015 after 9 patients were randomized. Of 50 patients in the everolimus group 2 did not start therapy; 3 additional patients discontinued Ever‐DHAP because of toxicity. Nine patients (20%) and 13 patients (28%) needed dose reductions in the first and second cycle of Ever‐DHAP, respectively. A delayed recovery &gt;14 days was observed in 2 patients (5%) in cycle 1 and in 6 patients (13%) in cycle 2. CTCAE grade IV toxicities occurred in 39 patients (95%) and 27 patients (75%) in cycle 1 and 2, respectively. All grade IV‐toxicities were hematological toxicities. Apheresis needed 1 day in 35 (80%) of the Ever‐DHAP patients and 2 days in 8 patients (18%). PBSC collection was successful in 38/42 documented patients receiving Ever‐DHAP (91%). After two cycles of therapy we observed a CT‐based CR in 12/45 patients of the everolimus group (27%) and in 2/9 patients of the placebo group (22%). A PET‐based CR was achieved by 22/39 patients of the everolimus group (56%) and by 2/8 patients of the placebo group (25%). In the everolimus group 2 patients had progressive disease (4%) and 3 died (7%, not related to Ever‐DHAP). Final results and additional analyses will be presented. Summary/Conclusion: With a CT‐based CR‐rate of 27% after two cycles of everolimus plus DHAP (PET‐based CR‐rate 56%), the trial did not meet the primary endpoint. Adding everolimus to time‐intensified DHAP is feasible, however, everolimus plus DHAP failed to show an improved efficacy.