Phase I Study of the Antibody-Drug Conjugate Brentuximab Vedotin Combined with Re-Induction Chemotherapy in Patients with CD30-Expressing Relapsed/Refractory Acute Myeloid Leukemia
Authors: Fathi Amir T. , Blonquist Traci M. , Emadi Ashkan , Brunner Andrew M. , Hobbs Gabriela S. , Hock Hanno , McAfee Steven L , Hasserjian Robert P. , Preffer Frederic I. , Moran Jenna A. , Bergeron Meghan , Foster Julia , Bertoli Christina , McGregor Kristin , Fishman Kaitlyn , Macrae Molly , Burke Meghan , Behnan Tanya T. , Som Tina T. , Ramos Aura Y. , Vartanian Megan K. , Lombardi Story Jennifer , Lesho Patricia , Duong Vu H. , Mann Mason , Lescinskas Christopher , Connolly Christine , Neuberg Donna S , Ballen Karen K. , Amrein Philip C. 
Published: October 2019

Abstract
Background: Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) consisting of an antibody specific for human CD30, an anti-microtubule agent monomethyl auristatin E (MMAE), and a protease-cleavable linker attaching MMAE to the antibody. BV is efficacious therapy against certain CD30-expressing malignancies, including classical Hodgkin lymphoma and anaplastic large cell lymphoma, and is currently approved for use in these diseases. We and others previously demonstrated CD30 expression on a sizeable proportion of primary AML samples as well as cell lines. Given this data, we conducted a phase I dose-escalation trial of BV in combination with re-induction chemotherapy (MEC) for patients with relapsed or refractory AML.
Methods: In this phase I, 3+3 cohort dose-escalation study, BV was administered 3 days prior to initiation of MEC re-induction for relapsed or refractory AML. Eligibility for enrollment included adults over age 18, adequate organ function, an ECOG performance status of ≤ 2, and a diagnosis of relapsed or refractory AML with > 20% CD30 expression (as assessed by immunohistochemistry or flow cytometric analysis). On day 1 of the trial, all enrolled participants were initiated on therapy with BV intravenously using three sequential dosing levels (0.9 mg/kg, 1.2 mg/kg, 1.8mg/kg). On day 3, patients were initiated on MEC re-induction chemotherapy (Mitoxantrone 10mg/m2 IV administration for five days [D3-8], etoposide 100mg/m2 IV D3-8, cytarabine 1000mg/m2 IV D3-8). The period of dose limiting toxicity (DLT) assessment occurred during the period of re-induction (approximately D1-35). Once dose escalation for BV reached a dose of 1.8 mg/kg IV, no further escalation would occur. An additional cohort of ten patients were to be treated at this maximum dose, or if a maximum tolerated dose (MTD) was reached, an additional 10 patients were to be treated at this dose. Thereafter, maintenance therapy with BV could be initiated, and administered IV every 21 days, as per dose level during prior re-induction, and continued for up to 12 months. Those eligible for stem cell transplant (SCT) were removed from study for this purpose.
Results: 22 eligible patients were enrolled on study. The median age was 58 (range 23-72); 15 (68%) were male, and 20 (91%) were Caucasian. 7 patients (32%) had secondary AML (6 with antecedent MDS and 1 with therapy related AML). 6 (27%) exhibited adverse risk karyotype. FLT3 mutations were seen in 7 (32%), NPM1 in 4 (18%), and CEBPA in 2 (9%). The median degree of blast CD30 expression in those assessed by flow cytometry was 92% (range 30-98%). 6 patients had refractory disease, while the remaining had relapsed AML at time of enrollment. 10 patients (46%) had undergone prior allogeneic stem cell transplantation (SCT), one of whom had undergone two prior stem cell transplants. Three patients were treated at dose level 1, 5 at dose level 2, and 4 at dose level 3. Two of the patients treated at dose level 2 were removed prior to end of DLT period due to lack of response and were replaced, and 1 patient treated at dose level 3 died due to infectious complications prior to end of DLT monitoring period and was replaced. No new attributable toxicities apart from that expected from MEC re-induction alone were seen with the combination therapy. No DLTs were detected, and the recommended phase 2 dose (RP2D) was deemed to be dose level 3 (1.8 mg/kg). An additional 10 patients were treated at the RP2D. Overall, 4 patients achieved a complete remission (CR) and 4 achieved a complete remission with incomplete hematologic recovery (CRi), for a composite remission rate (CCR) of 36% (8/22). Among the 14 patients treated at the RP2D of 1.8mg/kg, 6 achieved a CR or CRi (CCR 43%). Of the remaining cases, one was replaced prior to response assessment and the others experienced progressive disease. The degree of baseline CD30 expression by flow cytometry did not appear to predict for response in this phase 1 dose escalation study, although study of correlative samples is ongoing.
Conclusions: BV is well tolerated when administered in conjunction with conventional re-induction chemotherapy in patients with relapsed-refractory AML, in whom CD30 is an intriguing target. Adverse events on this study were predominantly expected and related to marrow suppression from MEC re-induction. No DLT was identified. Additional and larger studies are needed to more comprehensively assess the efficacy of CD30-targeted therapy in AML.

Disclosures
Fathi: Jazz: Honoraria; Boston Biomedical: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Emadi:NewLink Genetics: Research Funding. Brunner:Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Amrein:Takeda: Research Funding.