A Phase 1 First in Human (FIH) Study of AMG 701, an Anti-B-Cell Maturation Antigen (BCMA) Half-Life Extended (HLE) BiTE® (bispecific T-cell engager) Molecule, in Relapsed/Refractory (RR) Multiple Myeloma (MM)
Authors: Harrison Simon J , Minnema Monique C. , Lee Hans C. , Spencer Andrew , Kapoor Prashant , Madduri Deepu , Larsen Jeremy , Ailawadhi Sikander , Kaufman Jonathan L. , Raab Marc S. , Hari Parameswaran , Iida Shinsuke , Vij Ravi , Davies Faith E. , Lesley Robin , Upreti Vijay V. , Yang Zhao , Sharma Anjali , Minella Alex , Lentzsch Suzanne 
Published: November 2020

Aims: To evaluate AMG 701, a BiTE® molecule binding BCMA on MM cells and CD3 on T cells, in RR MM (Amgen, NCT03287908); primary objective was to evaluate safety and tolerability and estimate a biologically active dose; secondary objectives were to characterize pharmacokinetics (PK), anti-myeloma activity per IMWG criteria, and response duration.
Methods: Patients with MM RR or intolerant to ≥3 lines [proteasome inhibitor (PI), IMiD, anti-CD38 Ab as available] received AMG 701 IV infusions weekly in 4-week cycles until disease progression (PD). A 0.8-mg step dose was added prior to target doses ≥1.2 mg to prevent severe cytokine release syndrome (CRS). Target dose was achieved by day 8 or sooner with earlier escalation. Exclusion criteria included: solely extramedullary disease; prior allogeneic stem cell transplant (SCT) in the past 6 months; prior autologous SCT in the past 90 days; CNS involvement; prior anti-BCMA therapy. The first 3 cohorts (dose 5-45 μg) had 1 patient each, the next cohorts (0.14-1.2 mg) had 3-4 patients each, and subsequent cohorts (1.6-12 mg) were to have 3-10 patients each. Minimal residual disease (MRD) was measured by next-generation sequencing (NGS, ≤10-5 per IMWG) or flow cytometry (≤3×10-5).
Results: As of July 2, 2020, 75 patients received AMG 701. Patients had a median age of 63 years, a median time since diagnosis of 5.9 years, and a median (range) of 6 (1-25) prior lines of therapy; 27% of patients had extramedullary disease, 83% prior SCT, and 93% prior anti-CD38 Ab; 68% were triple refractory to a PI, an IMiD, and an anti-CD38 Ab. Median (Q1, Q3) treatment duration was 6.1 (3.1, 15.3) weeks and median follow-up on treatment was 1.7 (1.0, 3.7) months. Patients discontinued drug for PD (n=47), AEs (adverse events, n=4, 3 CRS, 1 CMV / PCP pneumonia), withdrew consent (4), other therapy (1), investigator discretion (1), and CNS disease (1); 17 patients remain on AMG 701.
The most common hematological AEs were anemia (43%), neutropenia (23%), and thrombocytopenia (20%). The most common non-hematological AEs were CRS (61%), diarrhea (31%), fatigue (25%), and fever (25%). CRS was mostly grade 1 (n=19) or 2 (n=21) per Lee Blood 2014 criteria. All grade 3 CRS (n=5, 7%) were assessed as dose-limiting toxicities (DLTs); all were reversible with corticosteroids and tocilizumab, with median duration of 2 days. CRS grade 3 drivers included transient LFT increases in 3 patients and hypoxia in 2 patients. Other DLTs were 1 case each of transient grade 3 atrial fibrillation, transient grade 3 acidosis, and grade 4 thrombocytopenia. Serious AEs (n=29, 39%) included infections (13), CRS (7), and asymptomatic pancreatic enzyme rise (2, no imaging changes, 1 treatment related). There were 4 deaths from AEs, none related to AMG 701 (2 cases of sepsis, 1 of retroperitoneal bleeding, and 1 of subdural hematoma). Reversible treatment-related neurotoxicity was seen in 6 patients, with median duration of 1 day, all grade 1-2, and associated with CRS in 4 patients.
The response rate was 36% (16/45) at doses of 3-12 mg; at ≤1.6 mg (n=27), there was 1 response at 0.8 mg in a patient with low baseline soluble BCMA (sBCMA). With earlier dose escalation with 9 mg, the response rate was 83% (5/6, 3 PRs, 2 VGPRs), with 4/5 responders being triple refractory and 1 DLT of grade 3 CRS in this group. Across the study, responses included 4 stringent CRs (3 MRD-negative, 1 not yet tested), 1 MRD-negative CR, 6 VGPRs, and 6 PRs (Table). Median (Q1, Q3) time to response was 1.0 (1.0, 1.9) month, time to best response was 2.8 (1.0, 3.7) months, and response duration was 3.8 (1.9, 7.4) months, with maximum duration of 23 months; responses were ongoing at last assessment in 14/17 patients (Figure). MRD was tested in 4 patients (3 sCR, 1 CR) and all were negative (3 by NGS, 1 by flow); MRD negativity was ongoing at last observations up to 20 months later. AMG 701 exhibited a favorable PK profile in its target patient population of RR MM, with AMG 701 exposures increasing in a dose-related manner. Patient baseline sBCMA levels were identified as a determinant of AMG 701 free drug exposures; at higher doses, encouraging preliminary responses were seen even at the higher end of baseline sBCMA values.
Summary: In this FIH study with ongoing dose escalation, AMG 701, an anti-BCMA BiTE® molecule, demonstrated a manageable safety profile, encouraging activity, and a favorable PK profile in patients with heavily pre-treated RR MM, supporting further evaluation of AMG 701.

Disclosures
Harrison: Janssen: Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; Haemalogix: Consultancy; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria. Minnema:Amgen: Honoraria; Servier: Honoraria; Gilead: Honoraria; Celgene Corporation: Honoraria, Research Funding; Janssen Cilag: Honoraria. Lee:Celgene: Consultancy, Research Funding; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech: Consultancy; Regeneron: Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Amgen: Consultancy, Research Funding. Spencer:AbbVie: Consultancy, Honoraria, Research Funding; Roche: Honoraria; Takeda: Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; HaemaLogiX: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria; Pharmamar: Research Funding. Kapoor:Cellectar: Consultancy; Amgen: Research Funding; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria. Madduri:Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Foundation Medicine: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Celgene: Consultancy, Honoraria. Larsen:Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ailawadhi:Cellectar: Research Funding; BMS: Research Funding; Medimmune: Research Funding; Amgen: Research Funding; Takeda: Honoraria; Janssen: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; Phosplatin: Research Funding. Kaufman:Amgen: Consultancy, Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria; AbbVie: Consultancy; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Tecnopharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi/Genyzme: Consultancy, Honoraria. Raab:Takeda: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hari:BMS: Consultancy; Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy; Incyte Corporation: Consultancy; Takeda: Consultancy. Iida:AbbVie: Research Funding; Merck Sharpe Dohme: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Sanofi: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Davies:Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: Honoraria; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lesley:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Upreti:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Yang:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Sharma:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Minella:Amgen Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Beam Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Lentzsch:Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Janssen: Consultancy; Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Magenta: Current equity holder in private company; Sanofi: Research Funding; Karyopharm: Research Funding; Celularity: Consultancy; Sorrento: Consultancy.

OffLabel Disclosure:
AMG 701, a half-life extended BiTE® (bispecific T-cell engager) molecule is an investigational agent for multiple myeloma.