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

Neoplasms Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01482377
• Other study ID #: BP27771
• Secondary ID: 2011-002698-53
• Status: Completed
• Phase: Phase 1
• First received: November 28, 2011
• Last updated: January 26, 2017
• Start date: December 2011
• Est. completion date: February 2016

Study information

• Verified date: January 2017
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 145
• Est. completion date: February 2016
• Est. primary completion date: February 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Neoplasms

Intervention

Drug:
• RO5479599
RO5479599 will be administered Q2W or Q3W (other regimen could be explored based on observations during dose escalation part).
• 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.
• Erlotinib
Erlotinib, at a dose of 150 mg will be administered.
• zirconium-89-labeled RO5479599
Single dose of radiolabeled drug will be administered.

Locations

Country	Name	City	State
Denmark	Rigshospitalet, Onkologisk Klinik	København Ø
Korea, Republic of	National Cancer Center	Gyeonggi-do
Korea, Republic of	Asan Medical Center	Seoul
Netherlands	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
Spain	Hospital del Mar; Servicio de Oncologia	Barcelona
Spain	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Barcelona
Spain	Centro Integral Oncologico Clara Campal (CIOCC); Dirección Médica	Madrid
Spain	Hospital Universitario Virgen del Rocio; Servicio de Oncologia	Sevilla
Spain	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

Denmark,  Korea, Republic of,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Adverse Events		Baseline up to 28 days after last dose (approximately 48 months)
Primary	Maximum Tolerated Dose (MTD) or Optimal Biological Dose (OBD) of RO5479599		Cycle 1 Day 1 (cycle length = 14 or 21 days) up to 28 days
Primary	Number of Participants With Dose Limiting Toxicities (DLTs)		Cycle 1 Day 1 (cycle length = 14 or 21 days) up to 28 days
Primary	Standardized Uptake Value (SUV) of 89ZrRO5479599 Determined by Positron Emission Tomography (PET) Scan Over Regions of Interest (ROI)		From baseline to Day 8
Secondary	Percentage Change From Baseline in Standardized Uptake Value (SUV) of 89ZrRO5479599 at Pharmacodynamic (PD) active dose as Determined by PET Scan		From baseline to Day 22
Secondary	Part A: Recommended Phase II Dose (RPTD) of RO5479599 in Monotherapy		Cycle 1 Day 1 (cycle length = 14 or 21 days) up to 28 days
Secondary	Part B: Recommended Phase II Dose of RO5479599 in Combination With Cetuximab		Cycle 1 Day 1 (cycle length = 14 or 21 days) up to 28 days
Secondary	Part C: Recommended Phase II Dose of RO5479599 in Combination With Erlotinib		Cycle 1 Day 1 (cycle length = 14 or 21 days) up to 28 days
Secondary	Percentage of Participants With Objective Response According to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1		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)
Secondary	Percentage of Participants With Disease Control According to RECIST version 1.1		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)
Secondary	Duration of Response According to RECIST version 1.1		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)
Secondary	Progression Free Survival According to RECIST version 1.1		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)
Secondary	Maximum Serum Concentration (Cmax) of RO5479599 for Q2W Schedule		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)
Secondary	Cmax of RO5479599 for Q3W Schedule		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)
Secondary	Trough Serum Concentration (Cmin) for Q2W Schedule		PreI (0 hr) on D1 of each cycle from Cy2 (up to 48 months overall) (Cycle length = 14 days)
Secondary	Cmin for Q3W Schedule		PreI (0 hr) on D1 of each cycle from Cy2 (up to 48 months overall) (Cycle length = 21 days)
Secondary	Time to Reach Maximum Serum Concentration (Tmax) of RO5479599 for Q2W Schedule		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)
Secondary	Tmax of RO5479599 for Q3W Schedule		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)
Secondary	Area Under the Plasma Concentration-Time Curve (AUC) of RO5479599 for Q2W Schedule		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)
Secondary	AUC of RO5479599 for Q3W Schedule		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)
Secondary	Clearance (CL) of RO5479599 for Q2W Schedule		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)
Secondary	CL of RO5479599 for Q3W Schedule		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)
Secondary	Volume of Distribution (Vd) of RO5479599 for Q2W Schedule		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)
Secondary	Vd of RO5479599 for Q3W Schedule		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)
Secondary	Accumulation Ratio of RO5479599 for Q2W Schedule		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)
Secondary	Accumulation Ratio of RO5479599 for Q3W Schedule		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)
Secondary	Terminal Elimination Half-Life (t1/2) of RO5479599 for Q2W Schedule		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)
Secondary	t1/2 of RO5479599 for Q3W Schedule		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)
Secondary	Serum Concentration of RO5479599 at Time of Tumor Progression (Cprog) for Q2W Schedule		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)
Secondary	Cprog of RO5479599 for Q3W Schedule		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)
Secondary	Serum Concentration of RO5479599 at the Time of Tumor Response for Q2W Schedule		At the time of objective response (up to 48 months)
Secondary	Serum Concentration of RO5479599 at the Time of Tumor Response for Q3W Schedule		At the time of objective response (up to 48 months)
Secondary	Serum Concentration of RO5479599 at the Time of DLT for Q2W Schedule		At the time of DLT (up to 28 days)
Secondary	Serum Concentration of RO5479599 at the Time of DLT for Q3W Schedule		At the time of DLT (up to 28 days)
Secondary	Serum Concentration of RO5479599 at the Time of Tumor and Skin Biopsy (Cb) for Q2W Schedule		PrI (0 hr) on Cy1D1 and on Cy1 Day 14 (Cycle length = 14 days)
Secondary	Cb of RO5479599 for Q3W Schedule		PrI (0 hr) on Cy1D1 and on Cy1 Day 21 (Cycle length = 21 days)
Secondary	Serum Concentration of RO5479599 at the Time of PET Scan (Cpet) for Q2W Schedule		PrI (0 hr) on Cy1D1, Cy1 Day 14, and Cy4 Day 14 (Cycle length = 14 days)
Secondary	Cpet of RO5479599 for Q3W Schedule		PrI (0 hr) on Cy1D1, Cy1 Day 21, and Cy3 Day 21 (Cycle length = 21 days)
Secondary	Serum Concentration of RO5479599 at Time of Infusion-Related Reactions (IRRs) for Q2W Schedule		At the time of IRR (up to 48 months)
Secondary	Serum Concentration of RO5479599 at Time of IRRs for Q3W Schedule		At the time of IRR (up to 48 months)
Secondary	Change from Baseline in T Lymphocytes Cell Count for Q2W Schedule		PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 14, and Cy4 Day 14 (Cycle length = 14 days)
Secondary	Change from Baseline in T lymphocytes Cell Count for Q3W Schedule		PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 21, and Cy3 Day 21 (Cycle length = 21 days)
Secondary	Change from Baseline in Natural Killer Cell Count for Q2W Schedule		PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 14, and Cy4 Day 14 (Cycle length = 14 days)
Secondary	Change from Baseline in Natural Killer Cell Count for Q3W Schedule		PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 21, and Cy3 Day 21 (Cycle length = 21 days)
Secondary	Change from Baseline in Macrophages Cell Count for Q2W Schedule		PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 14, and Cy4 Day 14 (Cycle length = 14 days)
Secondary	Change from Baseline in Macrophages Cell Count for Q3W Schedule		PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 21, and Cy3 Day 21 (Cycle length = 21 days)
Secondary	Change from Baseline in Cytokines Level for Q2W Schedule		PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 14, and Cy4 Day 14 (Cycle length = 14 days)
Secondary	Change from Baseline in Cytokines Level for Q3W Schedule		PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 21, and Cy3 Day 21 (Cycle length = 21 days)
Secondary	Change from Baseline in HER3 Expression for Q2W Schedule		PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 14, and Cy4 Day 14 (Cycle length = 14 days)
Secondary	Change from Baseline in HER3 Expression for Q3W Schedule		PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 21, and Cy3 Day 21 (Cycle length = 21 days)
Secondary	Change from Baseline in Phosphorylated HER3 Expression for Q2W Schedule		PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 14, and Cy4 Day 14 (Cycle length = 14 days)
Secondary	Change from Baseline in Phosphorylated HER3 Expression for Q3W Schedule		PrI (0 hr) on Cy1D1 (Baseline), Cy1 Day 21, and Cy3 Day 21 (Cycle length = 21 days)