Phase I dose-escalation study of brentuximab-vedotin combined with dexamethasone, high-dose cytarabine and cisplatin, as salvage treatment in relapsed/refractory classical Hodgkin lymphoma: The HOVON/LLPC Transplant BRaVE study

Abstract

Clinical activity of brentuximab vedotin (BV), an antiCD30 antibody-drug conjugate, has been demonstrated in relapsed/refractory classical Hodgkin Lymphoma (R/R cHL) in pivotal phase I and phase II studies. Adverse events ascribed to BV as single agent are mostly mild and reversible. Combining BV and chemotherapy prior to high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) might lower the tumor burden and decrease the relapse rate after HDC-ASCT and thus contribute to cure. Brentuximab vedotin has already been combined with standard therapy in a sequential strategy and concurrently with chemotherapy regimens such as ESHAP (etoposide, methylprednisolone, cytarabine and cisplatin) before HDC-ASCT, and resulted in a CMR rate of more than 75% prior to HDC-ASCT. However, the combination of BV with multi-agent chemotherapy can be associated with significant toxicity. Tumor burden reduction by a combination of BV and DHAP treatment is attractive because DHAP by itself is well tolerated in patients with R/R cHL and results in 20% complete remission (CR) and 70% partial remission [PR; based on conventional computed tomography (CT) scanning] and 50-60% metabolic CR (CMR) while stem cell mobilization potential is maintained. In this multicenter, openlabel, phase I dose-escalation study, patients aged 18 years or older with a histologically confirmed CD30 R/R cHL were treated with three cycles of BV-DHAP, followed by HDC (BEAM regimen: carmustine, etoposide, cytarabine and melphalan) with an ASCT rescue. Brentuximab vedotin was administered at the full dose of 1.8 mg/kg on the first day of each cycle of DHAP, with escalation of the dose of cisplatin and cytarabine. BV was combined with either 75% of the dose cisplatin on day 1 and 75% of cytarabine on day 2 [dose level (DL) 1], 75% cisplatin and 100% cytarabin (DL2) or full dose of all agents (DL3). Full-dose cisplatin was defined as 100 mg/m and full-dose cytarabin was defined as 2 g/m q 12 hours (2 doses). Dexamethasone 40 mg was given at day 1-4. Granulocyte-colony stimulating factor (G-CSF) (Neulasta) 6 mg fixed dose was given subcutaneously on day 5 of DHAP cycles 1 and 3 from DL2 onwards after prolonged neutropenia requiring delay of the next cycle was seen in 2 out of 3 patients treated at DL1. For stem cell mobilization, G-CSF 5 μg/kg was administered twice daily from day 10 of BV-DHAP cycle 2 until stem cell harvest. Sequential cohorts of 3 patients were treated in a 3+3 dose escalation scheme. Decisions regarding feasibility, dose escalation to the next cohort, and continuation or cessation were based on the occurrence of dose-limiting toxicity (DLT). DLT was defined as either: a) grade 3-4 non-hematologic toxicity, including neurotoxicity with laboratory abnormalities grade equal or greater than 3, only when present for more than two weeks or not returning to grade 0/1; infections only if grade 4; b) allcause death, with the exception of death due to cHL; c) delay of the second or third cycle of BV-DHAP by more than ten days due to neutropenia, despite use of growth factor prophylaxis. Enrollment at each dose level required a minimum of 3 patients and a maximum of 6 patients. After inclusion of 3-6 patients, inclusion to this particular dose level was discontinued until DLT occurrence had been determined at day 22 after start of cycle 3 for these patients. Dose escalation was stopped as soon as at least 2 patients experienced a DLT or when the highest planned dose level had been reached. Before proceeding to a higher dose level, the DLT data at the preceding dose level were reviewed by the Data Safety Monitoring Board (DSMB).