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
Gastrointestinal Cancers
Presenter J.E. Faris
Citation Annals of Oncology (2014) 25 (suppl_2): ii105-ii117. 10.1093/annonc/mdu193
Authors J.E. Faris1, C. Cruz2, K. Almhanna3, W. Messersmith4, J. Rodon2, D.P. Ryan5, J.A. Jung6, A. Fasanmade6, T. Wyant6, T. Kalebic6
  • 1Massachusetts General Hospital Cancer Center, Boston/US
  • 2Vall d'Hebron Institute of Oncology (VHIO), Barcelona/ES
  • 3Moffitt Cancer Center, Tampa/US
  • 4University of Colorado Cancer Center, Aurora/US
  • 5Massachusetts General Hospital, Boston/US
  • 6Takeda Pharmaceuticals International Co., Cambridge/US



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.