A Phase 1 Study of the Anti-CD37 Antibody-Drug Conjugate AGS67E in Advanced Lymphoid Malignancies. Interim Results

Introduction.  AGS67E, a fully human IgG2 antibody conjugated to the anti-tubulin agent  MMAE through a cleavable linker, targets CD37, a tetraspanin expressed by most B- and T- cell malignancies  (Pereira et al, Mol Cancer Ther; 14(7) 2015). Among normal hematopoietic cells, CD37 is expressed mostly on B lymphocytes and to a lesser extent on T lymphocytes, neutrophils, monocytes and a subset of early myeloid precursors.

Methods.  A phase 1 dose-escalation multicenter study is ongoing to evaluate safety, PK and anticancer activity of AGS67E given as monotherapy once every 3 weeks in patients with relapsed / refractory non-Hodgkin lymphoma without or with growth factor (GF) prophylaxis. Therapy is continued until progression or unacceptable toxicity.

Results. Overall 13 patients have been treated in 7 dose cohorts (0.05 to 1.2 mg/kg without GF and 1.2 mg/kg with GF). Diagnoses included: 10 B-cell lymphomas [5 diffuse large B cell lymphomas (DLBCL), 2 follicular lymphomas (FL), 1 mantle cell lymphoma, 1 Waldenström's macroglobulinemia, 1 small lymphocytic lymphoma and 3 T-cell lymphomas (2 mycosis fungoides, 1 peripheral T-cell lymphoma).  Median age was 59 (47-85) years. Patients received a median number of 2 (1-10) prior therapies.  MTD was exceeded at 1.2 mg/kg given without GF, with all 3 patients treated at this level developing grade 4 neutropenia 8 to 15 days after the first dose. No major non-hematological toxicities have been observed thus far.

Dose (mg/kg)	n	median n doses (Min-Max)	neutropenia  in cycle 1			other ≥Gr 3 related toxicities
			gr 4	gr 4 >7 days	Fever
0.05	1	11+	-	-	-	-
0.1	1	3	-	-	-	gr3 fall in cycle 3
0.3	1	2	-	-	-	-
0.6	1	3	-	-	-	-
1.2	3	5 (4-5+)	3	1	1	-
0.9 enrolling	3 (6)	2 (1-2)	2	1	-	-
1.2 with GF enrolling	6	2 (2-3)	-	-	-	-

+ = indicates that subjects are continuing to receive treatment

Objective responses were observed at the1.2 mg/kg dose level: one patient with DLBCL experienced a CR. The serum AGS67E concentrations indicated non-linear pharmacokinetics at and below 0.6 mg/kg dose levels. At 1.2 mg/kg, the half-life of AGS67E and free MMAE ranged from 1.44–3.08 days and 2.34–3.64 days, respectively.

Conclusions: AGS67E administered every three weeks demonstrates a favorable extra-medullary safety profile and signs of anti-lymphoma activity. Expansion cohorts are planned at the Maximum Tolerated Dose both without growth factor and with growth factor.