A Study Evaluating Safety, Pharmacokinetics, and Therapeutic Activity of RO6874281 as a Single Agent (Part A) or in Combination With Trastuzumab or Cetuximab (Part B or C)

Breast Cancer Clinical Trial

Official title:

An Open-Label, Multicenter, Dose-Escalation, Phase Ia/Ib Study to Evaluate Safety, Pharmacokinetics, and Therapeutic Activity of RO6874281, an Immunocytokine Consisting of Interleukin 2 Variant (IL-2v) Targeting Fibroblast Activation Protein-α (FAP), as a Single Agent (Part A) or in Combination With Trastuzumab or Cetuximab (Part B or C)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02627274
• Other study ID #: BP29842
• Secondary ID: 2015-002251-97
• Status: Completed
• Phase: Phase 1
• Start date: December 7, 2015
• Est. completion date: November 10, 2022

Study information

• Verified date: November 2022
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This first-in-human, open-label, multicenter, Phase Ia/Ib, adaptive, multiple ascending-dose study will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of RO6874281 as a single agent (Part A) or in combination with trastuzumab or cetuximab (Part B or C).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 134
• Est. completion date: November 10, 2022
• Est. primary completion date: November 10, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Radiologically measurable and clinically evaluable disease

• Absence of rapid disease progression or threat to vital organs or critical anatomical sites requiring urgent alternative medical intervention

• Confirmed at least one tumor lesion with location accessible to safely biopsy per clinical judgment (special requirements apply for Part C; Participants with only one target lesion and no non-target lesions can enroll after documented agreement with the Medical Monitor).

• Life expectancy of greater than or equal to (>=12) weeks

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1

• Participants with unilateral pleural effusion (other than non-small cell lung cancer [NSCLC] indication) should fulfill the following criteria for pulmonary and cardiac functions: Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification 0 - 1 level and New York Heart Association (NYHA) classification class 1 or better

• Forced expiratory volume 1 (FEV1) >70% and forced vital capacity (FVC) >70% of predicted value; participants with lung metastases should present with DLCO >60% of predicted value

• Adequate cardiovascular, hematological, liver and renal function

• All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure must have resolved to grade less than or equal to (<=) 1, except alopecia (any grade) and Grade 2 peripheral neuropathy

• Negative serum pregnancy test within 7 days prior to study treatment in premenopausal women and women less than (<) 12 months after menopause

• For women who are not postmenopausal and have not undergone surgical sterilization:

agreement to remain abstinent or use two adequate non-hormonal methods of contraception, including at least one method with a failure rate of <1 percent (%) per year, during the treatment period and for a period of time after the last dose of study drug(s) as defined in the protocol

• For men: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm during the treatment period and for at least for at least 2 months after the last dose of study treatment

• For Part A exclusively (RO6874281 monotherapy), confirmed advanced and/or metastatic solid tumor, with at least one tumor lesion of location accessible to biopsy per clinical judgment of the treating physician, and confirmed progression at baseline; for whom no standard therapy that would confer clinical benefit to the participant exists

• For Part B exclusively (RO6874281 in combination with trastuzumab), participants with metastatic or recurrent or locally advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer, as defined by the College of American Pathologists HER2 testing guidelines, who have progressed on at least two lines of HER2-directed therapies in the metastatic setting and the last therapy prior to going on study has to contain a HER2-directed antibody; baseline left ventricular ejection fraction (LVEF) of >=50% (measured by echocardiography) predose on Cycle 1 Day 1

• For Part C exclusively (RO6874281 in combination with cetuximab), participants with recurrent, unresectable or metastatic squamous cell carcinoma of the head and neck. Participants can have had standard or experimental treatment, including but not limited to radiation therapy, chemotherapy, or immunotherapy

• Participants with Gilbert's syndrome will be eligible for the study

Exclusion Criteria:

• History of, active, or suspicion of autoimmune disease (exceptions apply)

• Adverse events from prior anti-cancer therapy that have not resolved to Grade 1, except for alopecia, vitiligo, or endocrinopathies managed with replacement therapy

• Symptomatic or untreated central nervous system (CNS) metastases

• History of treated asymptomatic CNS metastases with any of the following: Metastases to the brain stem, midbrain, pons, medulla, cerebellum, or within 10 millimeters (mm) of the optic nerves and chiasm; history of intracranial or spinal cord hemorrhage; lacking radiographic demonstration of improvement upon the completion of CNS-directed therapy and evidence of progression between completion of therapy and the baseline radiographic study; ongoing requirement for dexamethasone; stereotactic or whole brain radiation within 28 days before the start of study treatment; last CNS radiographic study less than 4 weeks since completion of radiotherapy and less than 2 weeks since the discontinuation of corticosteroids; CNS metastases treated by resection or brain biopsy performed within 28 days before the start of study treatment

• Participants with an active second malignancy

• Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including diabetes mellitus, history of relevant pulmonary disorders, and known autoimmune diseases or other disease with ongoing fibrosis

• Participants (all indications) with confirmed bilateral pleural effusion and NSCLC participants with confirmed uni- or bilateral pleural effusion by X-ray are not eligible

• Significant cardiovascular/cerebrovascular disease within 6 months prior to Day 1 of study drug administration

• Active or uncontrolled infections

• Known human immunodeficiency virus (HIV) or known active hepatitis B virus or hepatitis C virus infection

• History of chronic liver disease or evidence of hepatic cirrhosis

• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding that give reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug

• Major surgery or significant traumatic injury <28 days prior to the first RO6874281 infusion (excluding biopsies) or anticipation of the need for major surgery during study treatment

• Dementia or altered mental status that would prohibit informed consent

• Pregnant or breastfeeding women

• Known hypersensitivity to any of the components of RO6874281

• Concurrent therapy with any other investigational drug

• Immune-related endocrinopathies

• Immunomodulating agents <28 days prior to first dose of study drug

• Treatment with systemic immunosuppressive medications

• Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy

• For Part B exclusively, known hypersensitivity to any of the components of trastuzumab

• For Part C exclusively, known hypersensitivity to any of the components of cetuximab

• For Parts A, B, and C, eligibility of participants who require blood transfusion before and after the start of the study treatment should be discussed by the Sponsor and investigator

• For Parts B and C, Participant eligibility for treatment with trastuzumab or cetuximab should be verified against trastuzumab or cetuximab labeling documents.

Related Conditions & MeSH terms

• Breast Cancer
• Cancer of Head and Neck
• Head and Neck Neoplasms
• Solid Tumor

Intervention

Drug:
• RO6874281
RO6874281 will be administered as per the schedule specified under arm description.
• Trastuzumab
Trastuzumab will be administered as per the schedule specified under arm description.
• Cetuximab
Cetuximab will be administered as per the schedule specified under arm description.

Locations

Country	Name	City	State
Belgium	UZ Antwerpen	Edegem
Canada	Juravinski Cancer Clinic; Department of Oncology	Hamilton	Ontario
Canada	Princess Margaret Cancer Center	Toronto	Ontario
Denmark	Rigshospitalet; Onkologisk Klinik	København Ø
France	Institut Bergonie; Oncologie	Bordeaux
France	Centre Georges Francois Leclerc	Dijon
France	Centre Leon Berard	Lyon
France	Institut Claudius Regaud; Departement Oncologie Medicale	Toulouse
France	Institut Gustave Roussy; Sitep	VILLEJUIF Cedex
Italy	IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica	Meldola	Emilia-Romagna
Italy	Azienda Socio Sanitaria Territoriale Niguarda (Ospedale Niguarda Ca' Granda); Oncologico -Onc.Falck	Milano	Lombardia
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori;S.S. Trattamento MedicoTumori dellaTesta e delCollo	Milano	Lombardia
Italy	Istituto Europeo di Oncologia; Svil. Nuovi Farmaci per Terapie Innovative	Milano	Lombardia
Italy	Ospedale Policlinico S. Matteo; Phase I Clinical Trial Unit and Experimental Therapy	Pavia	Lombardia
Netherlands	Antoni Van Leeuwenhoek Ziekenhuis; Gastro-Enterologie	Amsterdam
Netherlands	Erasmus MC	Rotterdam
Spain	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Barcelona
Spain	Clinica Universitaria de Navarra	Pamplona	Navarra
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	Guys and St Thomas NHS Foundation Trust, Guys Hospital	London
United Kingdom	Christie Hospital	Manchester
United States	The Ohio State University	Columbus	Ohio
United States	Banner MD Anderson Cancer Center	Greeley	Colorado
United States	UCSD - Moores Cancer Center	La Jolla	California
United States	Washington University; Division of Oncology	Saint Louis	Missouri
United States	University of Arizona Cancer Center	Tucson	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Denmark,  France,  Italy,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Dose-Limiting Toxicities (DLTs)		Day 1 up to Day 21
Primary	Maximum Tolerated Dose (MTD) of RO6874281		Day 1 up to Day 21
Primary	Optimal Biological Dose (OBD) of RO6874281		Day 1 up to Day 21
Primary	Recommended Dose for Further Development of RO6874281		Day 1 up to Day 21
Primary	Systemic Clearance (CL) of RO6874281		Day 1 up to 24 months
Primary	Volume of Distribution at Steady State (Vss) of RO6874281		Day 1 up to 24 months
Primary	Area Under the Concentration-Time Curve (AUC) of RO6874281		Day 1 up to 24 months
Primary	Maximum Observed Serum Concentration (Cmax) of RO6874281		Day 1 up to 24 months
Secondary	Number of T Cells in the Peripheral Blood		Day 1 up to 24 months
Secondary	Number of Natural Killer (NK) Cells in the Peripheral Blood		Day 1 up to 24 months
Secondary	Density of Cluster of Differentiation (CD)8+ Cells in Tumor Samples		Day 1 up to 24 months
Secondary	Density of CD3-/Perforin+ Cells in Tumor Samples		Day 1 up to 24 months
Secondary	Density of CD20 Cells in Tumor Samples		Day 1 up to 24 months
Secondary	Percentage of Participants With Overall Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)		Day 1 up to 24 months
Secondary	Percentage of Participants With Disease Control According to RECIST v1.1		Day 1 up to 24 months
Secondary	Progression-Free Survival (PFS) According to RECIST v1.1		Day 1 up to 24 months
Secondary	Percentage of Participants With Overall Response According to Modified RECIST		Day 1 up to 24 months
Secondary	Percentage of Participants With Disease Control According to Modified RECIST		Day 1 up to 24 months
Secondary	PFS According to Modified RECIST		Day 1 up to 24 months
Secondary	Percentage of Participants With Overall Response According to iRECIST		Day 1 up to 24 months
Secondary	Percentage of Participants With Disease Control According to iRECIST		Day 1 up to 24 months
Secondary	PFS According to iRECIST		Day 1 up to 24 months