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A Study of RO5479599 Alone or in Combination With Cetuximab or Erlotinib in Participants With Metastatic and/or Locally Advanced Malignant Human Epidermal Growth Factor Receptor (HER3) Expressing Solid Tumors of Epithelial Cell Origin

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01482377
First received: November 28, 2011
Last updated: January 26, 2017
Last verified: January 2017
  Purpose

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.


Condition Intervention Phase
Neoplasms
Drug: RO5479599
Drug: Cetuximab
Drug: Erlotinib
Drug: zirconium-89-labeled RO5479599
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Phase Ia/Ib, Open-Label, Multicenter, Dose-Escalation Study Followed by an Extension Phase to Evaluate the Safety, Pharmacokinetics and Activity of RO5479599, A Glycoengineered Antibody Against HER3, Administered Either Alone (Part A) or in Combination With Cetuximab (Part B) or in Combination With Erlotinib (Part C) in Patients With Metastatic and/or Locally Advanced Malignant HER3-Positive Solid Tumors of Epithelial Cell Origin

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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) ]

Enrollment: 145
Study Start Date: December 2011
Study Completion Date: February 2016
Primary Completion Date: February 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A: RO5479599 Dose Escalation
Participants will receive a dose of 100 milligrams (mg) RO5479599 followed by dose escalation from Day 1 of Cycle 1. RO5479599 dose will be escalated as monotherapy in approximately 6 cohorts with dose increments between cohorts of up to 100 percent (%) until MTD.
Drug: RO5479599
RO5479599 will be administered Q2W or Q3W (other regimen could be explored based on observations during dose escalation part).
Experimental: Part B: RO5479599 Dose Escalation + Cetuximab
Participants will receive RO5479599 in combination with cetuximab. Escalation of RO5479599 in combination with cetuximab will start in a standard 3+3 design until MTD/OBD is reached. If the initial combination is not tolerated, further cohorts will be dosed with the same dose of cetuximab and lower doses of RO5479599.
Drug: RO5479599
RO5479599 will be administered Q2W or Q3W (other regimen could be explored based on observations during dose escalation part).
Drug: Cetuximab
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.
Experimental: Part C: RO5479599 Dose Escalation + Erlotinib
Participants will receive RO5479599 in combination with erlotinib. Escalation of RO5479599 in combination with erlotinib will start in a standard 3+3 design until MTD/OBD is reached. If the initial combination is not tolerated, further cohorts will be dosed with the same dose of erlotinib and lower doses of RO5479599.
Drug: RO5479599
RO5479599 will be administered Q2W or Q3W (other regimen could be explored based on observations during dose escalation part).
Drug: Erlotinib
Erlotinib, at a dose of 150 mg will be administered.
Experimental: Imaging (IMG) Substudy
RO5479599 will be administered with zirconium- 89-labeled RO5479599.
Drug: RO5479599
RO5479599 will be administered Q2W or Q3W (other regimen could be explored based on observations during dose escalation part).
Drug: zirconium-89-labeled RO5479599
Single dose of radiolabeled drug will be administered.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

All Parts (A, B and C)

  • European Cooperative Oncology Group (ECOG) performance status 0-2
  • Histologically confirmed metastatic and/or locally advanced malignant HER3-expressing solid tumors of epithelial origin
  • Availability of tissue and willingness to perform fresh pretreatment biopsies
  • Participants for whom no standard therapy exists
  • All acute toxic effects of any prior radiotherapy, chemotherapy or surgical procedure must have resolved to Grade less than or equal to (</= 1), except for alopecia and Grade 2 peripheral neuropathy
  • Adequate hematological, renal and liver function
  • Participants with Gilbert's syndrome will be eligible for the study

Part B extension cohort: In addition to the above inclusion criteria, participants will be eligible if they have metastatic and/or locally advanced non-small cell lung cancer or squamous cell carcinoma of the head and neck or colorectal cancer (wild type with positive epidermal growth factor receptor [EGFR] expression)

Part C extension cohort: In addition to the above inclusion criteria, participants will be eligible only if they have metastatic and/or locally advanced squamous non-small cell lung cancer

Exclusion Criteria:

  • Known or clinically suspected central nervous system (CNS) primary tumors or metastases including leptomeningeal metastases. History or clinical evidence of CNS metastases unless they have been previously treated, are asymptomatic and have had no requirement for steroids or enzyme-inducing anticonvulsants in the last 14 days
  • Evidence of significant uncontrolled concomitant diseases or disorders
  • Active or uncontrolled infections
  • Known Human immuno deficiency virus (HIV) infection
  • Therapy with antibody or immunotherapy concurrently or within 14 days prior to first dose of study drug
  • Regular immunosuppressive therapy
  • Concurrent high dose of systemic corticosteroids (greater than (>) 20 milligrams per day [mg/day] dexamethasone or equivalent for > 7 consecutive days)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01482377

Locations
Denmark
Rigshospitalet, Onkologisk Klinik
København Ø, Denmark, 2100
Korea, Republic of
National Cancer Center
Gyeonggi-do, Korea, Republic of, 10408
Asan Medical Center
Seoul, Korea, Republic of, 05505
Netherlands
Antoni van Leeuwenhoek Ziekenhuis
Amsterdam, Netherlands, 1066 CX
Academ Ziekenhuis Groningen; Medical Oncology
Groningen, Netherlands, 9713 GZ
Erasmus Medisch Centrum Rotterdam; Lokatie Daniel den Hoed
Rotterdam, Netherlands, 3075EA
Utrecht University Medical Centre; Dept of Medical Oncology and UPC
Utrecht, Netherlands, 3584 CW
Spain
Hospital del Mar; Servicio de Oncologia
Barcelona, Spain, 08003
Hospital Univ Vall d'Hebron; Servicio de Oncologia
Barcelona, Spain, 08035
Centro Integral Oncologico Clara Campal (CIOCC); Dirección Médica
Madrid, Spain, 28050
Hospital Universitario Virgen del Rocio; Servicio de Oncologia
Sevilla, Spain, 41013
Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
Valencia, Spain, 46010
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01482377     History of Changes
Other Study ID Numbers: BP27771  2011-002698-53 
Study First Received: November 28, 2011
Last Updated: January 26, 2017

Additional relevant MeSH terms:
Erlotinib Hydrochloride
Cetuximab
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on February 28, 2017