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Phase Ib study of dulanermin combined with FOLFIRI (with or without bevacizumab [BV]) in previously treated patients (Pts) with metastatic colorectal cancer (mCRC).
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2012
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Disease ProgressionApoptosisPathologyCell DeathMcrc PtsPharmacotherapyPre-clinical PharmacologyMolecular PharmacologyGastrointestinal OncologyMetronomic TherapyToxicologyAnti-cancer AgentRadiation OncologyMolecular OncologyMedicineColorectal CancerMetastatic Colorectal CancerCancer TreatmentPharmacologyPhase Ib StudyAe IncidenceClinical PharmacologyOncologyDrug DiscoveryQuantitative Pharmacology
3543 Background: Dulanermin is a recombinant soluble human Apo2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) that activates apoptotic pathways by binding to the pro-apoptotic death receptors DR4 and 5. This is the final update of the study assessing the safety of dulanermin combined with FOLFIRI (± BV) in previously treated mCRC pts. Methods: This was a multicenter, open-label, dose-escalation and cohort expansion study. Dulanermin was administered intravenously in 14-day cycles on Days 1, 2 and 3 at 9 mg/kg or 18 mg/kg, with FOLFIRI (+ BV in pts not previously treated with BV) on Day 1. Dose-limiting toxicity (DLT) was assessed through 2 cycles (28 days). Adverse events (AE) were recorded through all cycles. Response was assessed with RECIST (v1.0). Results: A total of 27 pts received 1-48 cycles (median 10) of dulanermin with FOLFIRI (1 pt received BV). No DLTs were reported and no relationship between dulanermin dose level and AE incidence or severity was detected. The most frequent AEs reported as dulanermin-related were fatigue (37%), anemia (19%), diarrhea, nausea, stomatitis, and weight decreased (15% each). The most frequent Grade ≥3 AEs reported as dulanermin-related were fatigue (15%), anemia, febrile neutropenia and vomiting (7% each). Serious AEs reported as dulanermin-related included: vomiting, dehydration, and febrile neutropenia (1 pt each). Some of these events were reported as related to dulanermin and other study drugs. One pt died on study due to disease progression. Other reasons for discontinuation of study treatment included disease progression (21 pts, 78%), and physician’s decision and pt’s decision (2 pts each, 7%). One pt is still receiving treatment. Among the 27 pts, best responses included 6 (22%) partial responses (5 confirmed, 1 unconfirmed), 17 (63%) stable disease, 3 (11%) progressive disease and 1 (4%) pt with no on-study tumor assessment. Conclusions: The addition of dulanermin to FOLFIRI (± BV) was well tolerated in previously treated mCRC pts. AEs were similar to those previously reported for the chemotherapy alone. Tumor responses were consistent with treatment response to FOLFIRI in this patient population.