A Dose Escalation Phase Ia Study of Anti-CD20 Antibody Drug Conjugate, MRG001 in Relapsed/Refractory Advanced Non-Hodgkin Lymphom
Authors: Song Yuqin , Guo Ye , Wang Zhao , Wu Meng , Peng Wei , Sun Lei , Sun Jinghui , Li Maggie , Zhu Jun 
Published: November 2021

Abstract
Background: MRG001 is an antibody drug conjugate (ADC), which is composed of a chimeric anti-CD20 monoclonal antibody conjugated via a valine citrulline linker to monomethyl auristatin E (MMAE), an anti-microtubulin agent. In preclinical studies, MRG001 demonstrated significant tumor growth inhibition in rituximab-resistant non-Hodgkin's lymphoma (NHL) models. MRG001 is being evaluated in a first-in-human, open-label, multicenter Phase I study for the safety, tolerability, pharmacokinetics (PK) and preliminary antitumor activity in patients with CD20-positive relapsed or refractory (R/R) B-cell NHL.
Methods: MRG001 was evaluated as a monotherapy for the treatment of patients with confirmed CD20-positive R/R B-cell NHL. The study consists of Phase Ia dose escalation and Ib dose expansion. In the Phase Ia dose-escalation study utilizing a "3+3" design, patients with pathologically confirmed R/R NHL received single agent MRG001 intravenously once every 3 weeks (Q3W) for a maximum of 6 treatment cycles. Six dose levels ranging from 0.15 to 2.5 mg/kg were evaluated for safety, PK and preliminary antitumor activity to determine the MTD/RP2D.
Results: From June 25, 2019 to May 31, 2021, a total of 21 subjects with DLBCL (n=8), FL (n=12), and MZL (n=1) who met the eligibility criteria had received at least two cycles of MRG001. As of May 31, 2021, 18 subjects were off treatment and 3 subjects were still on treatment. There were 3 subjects enrolled into the 0.15, 0.3 , 0.6, 1.2 and 2.5 mg/kg cohort respectively, and 6 subjects enrolled into the 1.8 mg/kg cohort. Of the 21 subjects enrolled, 12 subjects were male and 9 subjects were female, with age ranging from 27 to 75 years old.
Among the 18 subjects who were off treatment, 5 had completed 6 cycles of treatment, and 13 had drug discontinuation (12 due to progression of disease and 1 subject due to withdrawal of the informed consent for personal reasons).
Commonly observed drug-related TEAEs were decreased white blood cell/neutrophil/lymphocyte counts, ALT/AST elevation, pyrexia, hypertension, increased LDH, QT prolongation, and thrombocytopenia.TEAEs (29 cases) ≥ Grade 3 were reported in 9 subjects, including 23 drug-related TEAEs in 8 subjects. The most commonly reported Grade 3 or above TRAEs were leukopenia/neutropenia, lymphopenia, hypertension, and ALT elevation. In the 2.5 mg/kg cohort, two subjects experienced drug-related toxicities that met the DLT definition per protocol, including 1 subject with Grade 3 hyperlipidemia and 1 subject with Grade 4 neutropenia that lasted 5 days. There was no death due to AEs.
PK samples of total antibody, MRG001 and MMAE were measured at predefined time points and the results showed that the C max and AUC of total antibody, MRG001 and MMAE increased with dose level increase. The T max of MMAE was non-linear to dose level increase, similar trends could be observed in two other parameters including C max and AUC 0-t, which suggested that MMAE was continuously released from MRG001.
Among 21 pts who had at least one tumor assessment, 1 CR (5%), 4 PR (19%), 9 SD (43%), and 7 PD (33%). The investigator assessed ORR was 24% and the DCR was 67%. In the starting dose 0.15 mg/kg cohort, one subject with FL acheived PR. Among six subjects (4 with DLBCL and 2 with FL) enrolled in the 1.8 mg/kg cohort, one DLBCL subject achieved CR and another subject with DLBCL achieved PR, ORR was 33.33% (2 out of 6). Three subjects were enrolled in the 2.5 mg/kg cohort, two subjects with FL had PR, both of them had DLT on cycle 1 and had dose reduction to 1.8 mg/kg from cycle 2, ORR was 66.7% (2 out of 3).
Conclusion: The dose escalation study of MRG001 has shown manageable safety profiles and encouraging preliminary antitumor activity in patients with NHL. Based on the safety, tolerability, and pharmacokinetic parameters of MRG001, 1.8 mg/kg was determined to be the RP2D and further investigation of MRG001 in patients with NHL is warranted.

Disclosures
Peng: Lepu Biopharma Co., Ltd.: Current Employment. Sun: Shanghai Miracogen Inc.: Current Employment. Sun: Shanghai Miracogen Inc.: Current Employment. Li: Shanghai Miracogen Inc.: Current Employment.