A Phase I Study Of An Anti-CD30 x Anti-CD16A Bispecific Tandab Antibody, AFM13, In Patients With Relapsed Or Refractory Hodgkin Lymphoma
Authors: Zhukovsky Eugene , Rothe Achim , von Tresckow Bastian , Topp Max , Younes Anas , Eichenauer Dennis A. , Hummel Horst , Reiners Katrin S. , Dietlein Markus , Kessler Joerg , Ravic Miroslav , Hucke Christian , Strandmann Elke Poggevon , Engert Andreas 
Published: October 2019

Abstract

Background
AFM13 is a bispecific TandAb antibody for the treatment of Hodgkin lymphoma (HL) and other CD30+ malignancies. AFM13 specifically targets both CD30, which is the antigen identifying HL tumor cells, and CD16A, for the recruitment of NK cells. Our preclinical data demonstrate a specific and potent anti-tumor activity mediated by the engagement of NK immune effector cells.

Methods
AFM13 was investigated in an open-label single-arm phase I dose escalation trial in patients with relapsed/refractory HL. The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, anti-tumor activity, and maximum tolerated dose (MTD). Each patient received 4 weekly doses of AFM13. Seven dose levels, from 0.01 to 7.0 mg/kg, were escalated in cohorts of 3 patients. In addition, one cohort of 4 patients received AFM13 twice a week at 4.5 mg/kg for 4 weeks.

Results
Twenty-eight (28) HL patients were enrolled, and these heavily pre-treated patients had a median number of six (6) prior therapies. 14/28 patients were refractory to their most recent therapy. 9/28 patients had a prior therapy with brentuximab vedotin. AFM13 was safe and well-tolerated, and did not reach the MTD. One dose-limiting toxicity (DLT) was observed at 0.5 mg/kg, and this dose cohort was expanded to 6 patients. No further DLTs were observed. The most frequent adverse events were infusion-related reactions (headache, fever, fatigue and myalgia) that often occurred after the first administration. Nearly all adverse events were short-lived. According to the Cheson criteria, 2 patients achieved partial responses and 13 patients achieved stable disease. In addition, AFM13 was active in brentuximab vedotin relapsing/refractory patients, with 7 out of 9 patients achieving stable disease after AFM13 treatment. The responses of the 13 patients who received AFM13 at and above the 1.5 mg/kg dose level were further analyzed for pharmacodynamic/anti-tumor activity correlations. In this group the drug exhibited substantial anti-tumor activity, with 8 out of the 13 patients experiencing a reduction in both tumor volume (as assessed by CT scan) and tumor activity (as assessed by FDG-PET scan imaging). Furthermore, 3 out of the 13 patients (23%) exhibited a reduction in tumor volume of more than 50%. The on-mechanism activity of the drug was further substantiated by the NK cell activation and soluble CD30 clearance pharmacodynamic parameters. Statistically significant correlations between increasing anti-tumor activity parameters (i.e. tumor volume reduction and FDG-PET SUV reduction) and the pharmacodynamic biomarkers were observed as: i) a dose-dependent increase in the activation of NK cells, and ii) a dose-dependent reduction in soluble CD30 levels. Variations in SUV were correlated with the number of activated NK cells (i.e. CD69+ cells) at baseline and 24 hours after the start of therapy with AFM13. The number of activated NK cells peaked 12 hrs after dosing, and dropped after 48 hrs. A decrease in SUV was observed at the highest level of activated NK cells, and was accompanied by a concomitant reduction in soluble CD30 levels. Furthermore, AFM13 exhibited a half-life of 1 day, representing a substantial increase relative to that of the alternative bispecific tandem scFv that is currently in clinical evaluation for hematological malignancies.

Conclusions
AFM13 has demonstrated good safety and encouraging anti-tumor activity. Furthermore, there is a solid scientific rationale suggesting that during phase I the anti-tumor potential of AFM13 was not fully realized. A compelling hypothesis for further exploration is whether we may detect much stronger activity, in refractory/relapsing HL patients, in a phase II study employing a pK-optimized regimen with an extended duration of therapy.

Disclosures:
Zhukovsky: Affimed Therapeutics AG: Employment, Equity Ownership. von Tresckow:Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Topp:Affimed Therapeutics AG: Consultancy. Ravic:Affimed Therapeutics AG: Consultancy. Hucke:Affimed Therapeutics AG: Consultancy. Engert:Affimed Therapeutics AG: Consultancy.