O-0009 - Phase I study of the investigational anti-guanylyl cyclase C (gcc) antibody-drug conjugate (adc) MLN0264 in adult patients with advanced gastrointes...
|Date||27 June 2014|
|Event||World GI 2014|
|Session||Presentation of selected abstracts|
|Topics|| Drug Development
|Citation||Annals of Oncology (2014) 25 (suppl_2): ii105-ii117. 10.1093/annonc/mdu193|
J.E. Faris1, C. Cruz2, K. Almhanna3, W. Messersmith4, J. Rodon2, D.P. Ryan5, J.A. Jung6, A. Fasanmade6, T. Wyant6, T. Kalebic6
GCC has been found to be expressed in approximately 95% of primary and metastatic colorectal cancers (CRCs), and a subset of gastric and pancreatic cancers. MLN0264 is an investigational ADC comprising a fully human antibody selectively targeting GCC linked to monomethyl auristatin E (MMAE) through a protease-cleavable linker (MMAE and linker technology licensed from Seattle Genetics). This first-in-human study has been designed to investigate the safety, MTD, pharmacokinetics, and preliminary antitumor activity of MLN0264 (NCT01577758).
Patients received MLN0264 via a 30-minute IV infusion on day 1 of 21-day cycles. Dose escalation proceeded using a Bayesian continual reassessment method in patients with various gastrointestinal malignancies, including gastric and pancreatic cancer. An expansion cohort at the MTD evaluated patients with metastatic CRC, including ≥6 with high GCC expression. AEs were assessed per NCI-CTCAE v4.03. Blood samples for pharmacokinetic assessment were collected. Responses were assessed per RECIST v1.1.
At data cut-off (January 17, 2014), 41 evaluable patients had received MLN0264, 19 during dose-escalation (0.3–2.4 mg/kg) and 25 in the expansion cohort (which includes 3 from 1.8 mg/kg dose-escalation cohort). Median age was 60 years (30-78); 27 were male and 14 female. Median number of prior lines of therapy was 5.5 (2–11); 93% had ≥3 prior lines. Patients on this study received a median of 2 treatment cycles of MLN0264 (1–12), with 22% receiving ≥4 cycles; 4 remain on treatment. Four patients had DLTs of grade 4 neutropenia. One patient treated at 1.8 mg/kg (MTD) experienced grade 4 neutropenia with fever. Three out of four patients who experienced DLTs have been treated at doses above the MTD. Two patients dosed at 2.1 mg/kg experienced DLTs of grade 4 neutropenia, one of which experienced also grade 3 QTc prolongation. One patient dosed at 2.4 mg/kg experienced grade 4 neutropenia. Per protocol, all DLTs required discontinuation, and resolved following treatment discontinuation. The MTD was determined to be 1.8 mg/kg. Among all 41 patients, when all doses were considered, 90% reported ≥1 AE of any grade, including fatigue (41%), nausea (41%), decreased appetite (39%), and diarrhea (34%). Grade ≥3 AEs were reported in 54% of patients, which included neutropenia (20%), hypokalemia (10%), diarrhea (7%), and anemia (7%). Serious AEs were reported in 15/41 (37%) patients. Study treatment discontinuations due to AEs were reported in 4/41 (10%) patients. MLN0264 was detectable in all patients in a dose-dependent manner. ADC was detectable in serum at the pre-infusion time of the next cycle (day 21) for patients dosed at ≥1.2 mg/kg. MMAE was detectable in a dose-dependent manner; peak concentration occurred approximately 2–3 days after each infusion. Objective response (PR) was seen in one patient with gastric carcinoma (1.8 mg/kg). Stable disease was seen in 16 patients, which lasted for ≥4 cycles in 4 patients, including 12 cycles in a patient with pancreatic cancer.
MLN0264 has shown a manageable safety profile in patients with advanced gastrointestinal malignancies receiving 1.8 mg/kg every 3 weeks (MTD). Preliminary data suggest antitumor activity in this population. Further investigation is planned.