A Phase I Study of Everolimus in Combination with Time-Intensified DHAP (Dexamethasone, High-Dose AraC [Cytarabine], Cisplatinum) in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma (cHL)
Authors: von Tresckow Bastian , Pluetschow Annette , Haverkamp Heinz , Vucinic Vladan , Rank Andreas , Topp Max S. , Feuring-Buske Michaela , Kobe Carsten , Kuhnert Georg , Böll Boris , Eichenauer Dennis A. , Sasse Stephanie , Fuchs Michael , Engert Andreas , Borchmann Peter 
Published: October 2019

Abstract
Introduction: The standard treatment for patients with relapsed or refractory (r/r) classical Hodgkin Lymphoma (cHL) is salvage chemotherapy followed by autologous stem cell transplantation (ASCT). The best outcome from the transplant is expected in patients who achieve complete remission (CR) after the salvage chemotherapy. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor that has shown activity and an acceptable toxicity profile in patients with r/r cHL (Johnston PB et al. Am J Hematol 2010; Johnston PB et al. ISHL-9 2013). We therefore aim to improve the CR rate after salvage by an enforced salvage regimen consisting of everolimus plus time-intensified standard DHAP (Dexamethasone, High-Dose AraC [Cytarabine], Cisplatinum).
Methods: We conducted a phase I trial of everolimus plus DHAP (ever-DHAP) for patients with r/r cHL eligible for ASCT to assess the recommended phase II dose (RPTD) of oral everolimus in this combination. Everolimus was administered for 14 days in each DHAP cycle starting from one day before DHAP. The second cycle of ever-DHAP was scheduled to start at day 14 of cycle one. Patients received two cycles of ever-DHAP. Everolimus dose levels of 2.5mg, 5mg, 7.5mg and 10mg were assessed in a modified 3+3 design. Generally, dose-limiting toxicity (DLT) was defined as CTCAE grade III/IV toxicity or unsuccessful stem cell mobilization. However, grade III/IV non-hematological toxicities known from DHAP were only counted as DLT from second occurrence in any patient onwards. Grade III/IV hematological toxicities were only counted as DLTs in case of prolonged time to recovery. Restaging by (PET)-CT was performed at day 21 of the second cycle given that the patient had recovered; PET was mandatory for all patients not achieving a CR in the CT scan. The rate of patients experiencing DLTs during 2 cycles of the combination therapy was the primary endpoint of the study. Secondary endpoints included adverse events, tumor related results of therapy or death, treatment administration, time to recovery after end of treatment and stem cell mobilization.
Results: 14 patients were recruited between August 2012 and January 2014, all patients received at least one dose of everolimus. The median age was 33.5 years; six were female and eight were male. Eleven patients presented with stage III/IV disease. Overall, treatment was well tolerated. Two patients (both at the 7.5mg level) had a premature treatment termination and did not receive the 2nd cycle, one patient due to ototoxicity of grade I at investigator’s discretion and one patient due to neurotoxicity of grade III/IV. One additional patient (7.5mg cohort) suffered from ototoxicity of grade III/IV between end of treatment and restaging. Both grade III/IV toxicities were pre-defined as known from DHAP, thus they were not considered dose limiting at this first occurrence. No further non-hematological grade III/IV adverse events were reported. All patients but one experienced grade III/IV thrombocytopenia and leukopenia. No DLTs occurred and therefore 10mg of everolimus/day was chosen as RPTD. Duration of induction therapy including restaging after two cycles was 35-54 days. All patients who completed the 1st treatment cycle (n=13) had adequate stem cell mobilization (CD34+ cell count 2.9 - 31.1 x 106/kg; median 10 x 106/kg). So far one death occurred in a patient with pneumococcal sepsis one year after restaging. Responses according to CT scan in 12 patients who received two cycles of ever-DHAP were CR in 3 patients, CR unconfirmed (CRu) in 3 patients, partial remission (PR) in 5 patients and stable disease (SD) in 1 patient. This accounts for a CR/CRu rate of 50% (6/12) and an overall response rate of 92% (11/12). A PET scan was performed in 4 of 6 patients with CR/CRu; all had a negative PET (Deauville 1). In the 6 patients not achieving a CR/CRu 5 patients had a PET scan; 4 were PET positive (2 patients with Deauville 4 and 5 each) and 1 was PET negative (Deauville 1).
Conclusions: Ever-DHAP with 10mg everolimus/day is safe and feasible in patients with r/r cHL. Based on the results of this phase I trial a randomized, placebo-controlled trial of ever-DHAP has been initiated and is currently recruiting.

Disclosures
von Tresckow: Takeda: Honoraria, Travel grants, Travel grants Other; Novartis: Honoraria, Research Funding. Off Label Use: Everolimus in relapsed or refractory Hodgkin Lymphoma. Topp:Affimed: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. Engert:Millennium: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Affimed: Consultancy. Borchmann:Takeda: Honoraria, Research Funding, Travel grants Other.