This dose-escalating study consists of 3 parts (A, B and C) and will evaluate the safety, pharmacokinetics and efficacy of RO5479599, alone or in combination with cetuximab or erlotinib, in participants with metastatic and/or locally advanced malignant HER3-positive solid tumors. Cohorts of participants will receive escalating doses of intravenous RO5479599 as monotherapy (Part A) or in combination with cetuximab (in Part B) or with erlotinib (in Part C) followed by an extension phase for each part. In an imaging substudy, participants will receive one or two doses of zirconium-89-labeled RO5479599 (89ZrRO5479599) in addition to unlabeled RO5479599 to evaluate the in vivo biodistribution and organ pharmacokinetics of RO5479599.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
145
RO5479599 will be administered Q2W or Q3W (other regimen could be explored based on observations during dose escalation part).
Cetuximab will be administered via intravenous (IV) infusion at a starting dose of 400 mg/m\^2 for the first infusion, followed by doses of 250 mg/m\^2 for subsequent infusions.
Erlotinib, at a dose of 150 mg will be administered.
Single dose of radiolabeled drug will be administered.
Rigshospitalet, Onkologisk Klinik
København Ø, Denmark
Antoni van Leeuwenhoek Ziekenhuis
Amsterdam, Netherlands
Academ Ziekenhuis Groningen; Medical Oncology
Groningen, Netherlands
Erasmus Medisch Centrum Rotterdam; Lokatie Daniel den Hoed
Rotterdam, Netherlands
Utrecht University Medical Centre; Dept of Medical Oncology and UPC
Utrecht, Netherlands
National Cancer Center
Gyeonggi-do, South Korea
Asan Medical Center
Seoul, South Korea
Hospital del Mar; Servicio de Oncologia
Barcelona, Barcelona, Spain
Hospital Univ Vall d'Hebron; Servicio de Oncologia
Barcelona, Barcelona, Spain
Centro Integral Oncologico Clara Campal (CIOCC); Dirección Médica
Madrid, Madrid, Spain
...and 2 more locations
Percentage of Participants With Adverse Events
Time frame: Baseline up to 28 days after last dose (approximately 48 months)
Maximum Tolerated Dose (MTD) or Optimal Biological Dose (OBD) of RO5479599
Time frame: Cycle 1 Day 1 (cycle length = 14 or 21 days) up to 28 days
Number of Participants With Dose Limiting Toxicities (DLTs)
Time frame: Cycle 1 Day 1 (cycle length = 14 or 21 days) up to 28 days
Standardized Uptake Value (SUV) of 89ZrRO5479599 Determined by Positron Emission Tomography (PET) Scan Over Regions of Interest (ROI)
Time frame: From baseline to Day 8
Percentage Change From Baseline in Standardized Uptake Value (SUV) of 89ZrRO5479599 at Pharmacodynamic (PD) active dose as Determined by PET Scan
Time frame: From baseline to Day 22
Part A: Recommended Phase II Dose (RPTD) of RO5479599 in Monotherapy
Time frame: Cycle 1 Day 1 (cycle length = 14 or 21 days) up to 28 days
Part B: Recommended Phase II Dose of RO5479599 in Combination With Cetuximab
Time frame: Cycle 1 Day 1 (cycle length = 14 or 21 days) up to 28 days
Part C: Recommended Phase II Dose of RO5479599 in Combination With Erlotinib
Time frame: Cycle 1 Day 1 (cycle length = 14 or 21 days) up to 28 days
Percentage of Participants With Objective Response According to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Time frame: From screening to disease progression, death, withdrawal, or end of study (assessed at screening, then every eighth week for two weekly schedule [Q2W] and every ninth week for three weekly schedule [Q3W] up to approximately 48 months)
Percentage of Participants With Disease Control According to RECIST version 1.1
Time frame: From screening to disease progression, death, withdrawal, or end of study (assessed at screening, then every eighth week for Q2W and every ninth week for Q3W up to approximately 48 months)
Duration of Response According to RECIST version 1.1
Time frame: From screening to disease progression, death, withdrawal, or end of study (assessed at screening, then every eighth week for Q2W and every ninth week for Q3W up to approximately 48 months)
Progression Free Survival According to RECIST version 1.1
Time frame: From screening to disease progression, death, withdrawal, or end of study (assessed at screening, then every eighth week for Q2W and every ninth week for Q3W up to approximately 48 months)
Maximum Serum Concentration (Cmax) of RO5479599 for Q2W Schedule
Time frame: Pre-infusion (PrI, 0 hours [hr]) & end of infusion (EOI, 1.5 hr) on each 2-week cycle (Cy); 2, 5 hr post-infusion (PoI) on Cy1 Day 1 (D1), Cy1 Days 2, 3, 5, 8, 12; 2 hr PoI on Cy4D1; Cy4 Days 2, 3, 5, 8; Cy8 Days 2, 5, 8 (up to 48 months overall)
Cmax of RO5479599 for Q3W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 3-week Cy; 3 hr PoI on Cy1 D1, Cy1 Days 2, 4, 8, 12, 14, 19, 21; 3 hr PoI on Cy4 D1, Cy8 D1; Days 2, 4, 8, 12, 14, 19, 21 on Cy4 and Cy8 (up to 48 months overall)
Trough Serum Concentration (Cmin) for Q2W Schedule
Time frame: PreI (0 hr) on D1 of each cycle from Cy2 (up to 48 months overall) (Cycle length = 14 days)
Cmin for Q3W Schedule
Time frame: PreI (0 hr) on D1 of each cycle from Cy2 (up to 48 months overall) (Cycle length = 21 days)
Time to Reach Maximum Serum Concentration (Tmax) of RO5479599 for Q2W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 2-week Cy; 2, 5 hr PoI on Cy1 D1, Cy1 Days 2, 3, 5, 8, 12; 2 hr PoI on Cy4D1; Cy4 Days 2, 3, 5, 8; Cy8 Days 2, 5, 8 (up to 48 months overall)
Tmax of RO5479599 for Q3W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 3-week Cy; 3 hr PoI on Cy1 D1, Cy1 Days 2, 4, 8, 12, 14, 19, 21; 3 hr PoI on Cy4 D1, Cy8 D1; Days 2, 4, 8, 12, 14, 19, 21 on Cy4 and Cy8 (up to 48 months overall)
Area Under the Plasma Concentration-Time Curve (AUC) of RO5479599 for Q2W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 2-week Cy; 2, 5 hr PoI on Cy1 D1, Cy1 Days 2, 3, 5, 8, 12; 2 hr PoI on Cy4D1; Cy4 Days 2, 3, 5, 8; Cy8 Days 2, 5, 8 (up to 48 months overall)
AUC of RO5479599 for Q3W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 3-week Cy; 3 hr PoI on Cy1 D1, Cy1 Days 2, 4, 8, 12, 14, 19, 21; 3 hr PoI on Cy4 D1, Cy8 D1; Days 2, 4, 8, 12, 14, 19, 21 on Cy4 and Cy8 (up to 48 months overall)
Clearance (CL) of RO5479599 for Q2W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 2-week Cy; 2, 5 hr PoI on Cy1 D1, Cy1 Days 2, 3, 5, 8, 12; 2 hr PoI on Cy4D1; Cy4 Days 2, 3, 5, 8; Cy8 Days 2, 5, 8 (up to 48 months overall)
CL of RO5479599 for Q3W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 3-week Cy; 3 hr PoI on Cy1 D1, Cy1 Days 2, 4, 8, 12, 14, 19, 21; 3 hr PoI on Cy4 D1, Cy8 D1; Days 2, 4, 8, 12, 14, 19, 21 on Cy4 and Cy8 (up to 48 months overall)
Volume of Distribution (Vd) of RO5479599 for Q2W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 2-week Cy; 2, 5 hr PoI on Cy1 D1, Cy1 Days 2, 3, 5, 8, 12; 2 hr PoI on Cy4D1; Cy4 Days 2, 3, 5, 8; Cy8 Days 2, 5, 8 (up to 48 months overall)
Vd of RO5479599 for Q3W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 3-week Cy; 3 hr PoI on Cy1 D1, Cy1 Days 2, 4, 8, 12, 14, 19, 21; 3 hr PoI on Cy4 D1, Cy8 D1; Days 2, 4, 8, 12, 14, 19, 21 on Cy4 and Cy8 (up to 48 months overall)
Accumulation Ratio of RO5479599 for Q2W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 2-week Cy; 2, 5 hr PoI on Cy1 D1, Cy1 Days 2, 3, 5, 8, 12; 2 hr PoI on Cy4D1; Cy4 Days 2, 3, 5, 8; Cy8 Days 2, 5, 8 (up to 48 months overall)
Accumulation Ratio of RO5479599 for Q3W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 3-week Cy; 3 hr PoI on Cy1 D1, Cy1 Days 2, 4, 8, 12, 14, 19, 21; 3 hr PoI on Cy4 D1, Cy8 D1; Days 2, 4, 8, 12, 14, 19, 21 on Cy4 and Cy8 (up to 48 months overall)
Terminal Elimination Half-Life (t1/2) of RO5479599 for Q2W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 2-week Cy; 2, 5 hr PoI on Cy1 D1, Cy1 Days 2, 3, 5, 8, 12; 2 hr PoI on Cy4D1; Cy4 Days 2, 3, 5, 8; Cy8 Days 2, 5, 8 (up to 48 months overall)
t1/2 of RO5479599 for Q3W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 3-week Cy; 3 hr PoI on Cy1 D1, Cy1 Days 2, 4, 8, 12, 14, 19, 21; 3 hr PoI on Cy4 D1, Cy8 D1; Days 2, 4, 8, 12, 14, 19, 21 on Cy4 and Cy8 (up to 48 months overall)
Serum Concentration of RO5479599 at Time of Tumor Progression (Cprog) for Q2W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 2-week Cy; 2, 5 hr PoI on Cy1 D1, Cy1 Days 2, 3, 5, 8, 12; 2 hr PoI on Cy4D1; Cy4 Days 2, 3, 5, 8; Cy8 Days 2, 5, 8 (up to 48 months overall)
Cprog of RO5479599 for Q3W Schedule
Time frame: PrI (0 hr) & EOI (1.5 hr) on each 3-week Cy; 3 hr PoI on Cy1 D1, Cy1 Days 2, 4, 8, 12, 14, 19, 21; 3 hr PoI on Cy4 D1, Cy8 D1; Days 2, 4, 8, 12, 14, 19, 21 on Cy4 and Cy8 (up to 48 months overall)
Serum Concentration of RO5479599 at the Time of Tumor Response for Q2W Schedule
Time frame: At the time of objective response (up to 48 months)
Serum Concentration of RO5479599 at the Time of Tumor Response for Q3W Schedule
Time frame: At the time of objective response (up to 48 months)
Serum Concentration of RO5479599 at the Time of DLT for Q2W Schedule
Time frame: At the time of DLT (up to 28 days)
Serum Concentration of RO5479599 at the Time of DLT for Q3W Schedule
Time frame: At the time of DLT (up to 28 days)
Serum Concentration of RO5479599 at the Time of Tumor and Skin Biopsy (Cb) for Q2W Schedule
Time frame: PrI (0 hr) on Cy1D1 and on Cy1 Day 14 (Cycle length = 14 days)
Cb of RO5479599 for Q3W Schedule
Time frame: PrI (0 hr) on Cy1D1 and on Cy1 Day 21 (Cycle length = 21 days)
Serum Concentration of RO5479599 at the Time of PET Scan (Cpet) for Q2W Schedule
Time frame: PrI (0 hr) on Cy1D1, Cy1 Day 14, and Cy4 Day 14 (Cycle length = 14 days)
Cpet of RO5479599 for Q3W Schedule
Time frame: PrI (0 hr) on Cy1D1, Cy1 Day 21, and Cy3 Day 21 (Cycle length = 21 days)
Serum Concentration of RO5479599 at Time of Infusion-Related Reactions (IRRs) for Q2W Schedule
Time frame: At the time of IRR (up to 48 months)
Serum Concentration of RO5479599 at Time of IRRs for Q3W Schedule
Time frame: At the time of IRR (up to 48 months)
Change from Baseline in T Lymphocytes Cell Count for Q2W Schedule
Time frame: PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 14, and Cy4 Day 14 (Cycle length = 14 days)
Change from Baseline in T lymphocytes Cell Count for Q3W Schedule
Time frame: PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 21, and Cy3 Day 21 (Cycle length = 21 days)
Change from Baseline in Natural Killer Cell Count for Q2W Schedule
Time frame: PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 14, and Cy4 Day 14 (Cycle length = 14 days)
Change from Baseline in Natural Killer Cell Count for Q3W Schedule
Time frame: PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 21, and Cy3 Day 21 (Cycle length = 21 days)
Change from Baseline in Macrophages Cell Count for Q2W Schedule
Time frame: PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 14, and Cy4 Day 14 (Cycle length = 14 days)
Change from Baseline in Macrophages Cell Count for Q3W Schedule
Time frame: PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 21, and Cy3 Day 21 (Cycle length = 21 days)
Change from Baseline in Cytokines Level for Q2W Schedule
Time frame: PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 14, and Cy4 Day 14 (Cycle length = 14 days)
Change from Baseline in Cytokines Level for Q3W Schedule
Time frame: PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 21, and Cy3 Day 21 (Cycle length = 21 days)
Change from Baseline in HER3 Expression for Q2W Schedule
Time frame: PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 14, and Cy4 Day 14 (Cycle length = 14 days)
Change from Baseline in HER3 Expression for Q3W Schedule
Time frame: PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 21, and Cy3 Day 21 (Cycle length = 21 days)
Change from Baseline in Phosphorylated HER3 Expression for Q2W Schedule
Time frame: PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 14, and Cy4 Day 14 (Cycle length = 14 days)
Change from Baseline in Phosphorylated HER3 Expression for Q3W Schedule
Time frame: PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 21, and Cy3 Day 21 (Cycle length = 21 days)
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