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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)

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ClinicalTrials.gov Identifier: NCT02627274
Recruitment Status : Recruiting
First Posted : December 10, 2015
Last Update Posted : February 28, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief 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).

Condition or disease Intervention/treatment Phase
Solid Tumor Breast Cancer Cancer of Head and Neck Drug: RO6874281 Drug: Trastuzumab Drug: Cetuximab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 205 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : December 7, 2015
Estimated Primary Completion Date : May 19, 2020
Estimated Study Completion Date : May 19, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Part A: RO6874281 Monotherapy
Dose Escalation: RO6874281 will be administered as an intravenous (IV) infusion. The starting dose regimen of RO6874281 as a single agent will be 5 milligrams (mg) once weekly (QW). Different regimens may be explored based on the emerging safety, PK, and PD data of RO6874281 and may be tested in parallel. Participants will be treated with RO6874281 until disease progression, unacceptable toxicities, or withdrawal of consent. Participants may continue treatment with RO6874281 for a maximum of 24 months.
Drug: RO6874281
RO6874281 will be administered as per the schedule specified under arm description.

Experimental: Part B: RO6874281 in Combination with Trastuzumab

Dose Escalation: RO6874281 will be administered as an IV infusion. RO6874281 will be administered QW for the first 4 administrations, then Q2W. The standard dose for trastuzumab will be a loading dose of 6 milligrams per kilogram (mg/kg) followed by a maintenance dose of 4 mg/kg from Cycle 2 in a Q2W regimen. Different regimens may be explored based on the emerging safety, PK, and PD data of RO6874281 and may be tested in parallel. Participants will be treated with RO6874281 in combination with trastuzumab until disease progression, unacceptable toxicities, or withdrawal of consent. Participants may continue treatment with RO6874281 in combination with trastuzumab for a maximum of 24 months.

Extension Phase: When the MTD and/or the OBD and/or the recommended dose for further development of RO6874281 is defined, participants will receive the MTD and/or the OBD and/or the recommended dose for further development of RO6874281.

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

Drug: Trastuzumab
Trastuzumab will be administered as per the schedule specified under arm description.
Other Name: Herceptin

Experimental: Part C: RO6874281 in Combination with Cetuximab

RO6874281 will be administered as an IV infusion. The starting dose regimen of RO6874281 in combination with cetuximab will be 5 mg QW for the first 4 administrations, then Q2W. Cetuximab will be administered Q2W at 500 milligrams per square meter (mg/m^2). Different regimens may be explored based on the emerging safety, PK, and PD data of RO6874281 and may be tested in parallel. Participants will be treated with RO6874281 in combination with cetuximab until disease progression, unacceptable toxicities, or withdrawal of consent. Participants may continue treatment with RO6874281 in combination with cetuximab for a maximum of 24 months.

Extension Phase: When the MTD and/or the OBD and/or the recommended dose for further development of RO6874281 is defined, participants will receive the MTD and/or the OBD and/or the recommended dose for further development of RO6874281.

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

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




Primary Outcome Measures :
  1. Percentage of Participants With Dose-Limiting Toxicities (DLTs) [ Time Frame: Day 1 up to Day 21 ]
  2. Maximum Tolerated Dose (MTD) of RO6874281 [ Time Frame: Day 1 up to Day 21 ]
  3. Optimal Biological Dose (OBD) of RO6874281 [ Time Frame: Day 1 up to Day 21 ]
  4. Recommended Dose for Further Development of RO6874281 [ Time Frame: Day 1 up to Day 21 ]
  5. Systemic Clearance (CL) of RO6874281 [ Time Frame: Day 1 up to 24 months ]
  6. Volume of Distribution at Steady State (Vss) of RO6874281 [ Time Frame: Day 1 up to 24 months ]
  7. Area Under the Concentration-Time Curve (AUC) of RO6874281 [ Time Frame: Day 1 up to 24 months ]
  8. Maximum Observed Serum Concentration (Cmax) of RO6874281 [ Time Frame: Day 1 up to 24 months ]

Secondary Outcome Measures :
  1. Number of T Cells in the Peripheral Blood [ Time Frame: Day 1 up to 24 months ]
  2. Number of Natural Killer (NK) Cells in the Peripheral Blood [ Time Frame: Day 1 up to 24 months ]
  3. Density of Cluster of Differentiation (CD)8+ Cells in Tumor Samples [ Time Frame: Day 1 up to 24 months ]
  4. Density of CD3-/Perforin+ Cells in Tumor Samples [ Time Frame: Day 1 up to 24 months ]
  5. Density of CD20 Cells in Tumor Samples [ Time Frame: Day 1 up to 24 months ]
  6. Percentage of Participants With Overall Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) [ Time Frame: Day 1 up to 24 months ]
  7. Percentage of Participants With Disease Control According to RECIST v1.1 [ Time Frame: Day 1 up to 24 months ]
  8. Progression-Free Survival (PFS) According to RECIST v1.1 [ Time Frame: Day 1 up to 24 months ]
  9. Percentage of Participants With Overall Response According to Modified RECIST [ Time Frame: Day 1 up to 24 months ]
  10. Percentage of Participants With Disease Control According Modified RECIST [ Time Frame: Day 1 up to 24 months ]
  11. PFS According to Modified RECIST [ Time Frame: Day 1 up to 24 months ]


Information from the National Library of Medicine

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

Inclusion Criteria:

  • Radiologically measurable and clinically evaluable disease
  • 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
  • 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:

  • Rapid disease progression or threat to vital organs or critical anatomical sites requiring urgent alternative medical intervention
  • 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
  • Tumor infiltration into the thoracic great vessels and/or mediastinal structures or cavitations of pulmonary lesions
  • 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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02627274


Contacts
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Contact: Reference Study ID Number: BP29842 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com

Locations
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United States, Arizona
University of Arizona Cancer Center Recruiting
Tucson, Arizona, United States, 85719
United States, California
UCSD - Moores Cancer Center Recruiting
La Jolla, California, United States, 92037
United States, Colorado
University of Colorado Hospital - Anschutz Cancer Pavilion Terminated
Aurora, Colorado, United States, 80045
United States, New York
Memorial Sloan Kettering Terminated
New York, New York, United States, 10065
Belgium
UZ Antwerpen Not yet recruiting
Edegem, Belgium, 2650
Denmark
Rigshospitalet; Onkologisk Klinik Active, not recruiting
København Ø, Denmark, 2100
France
Centre Georges Francois Leclerc Recruiting
Dijon, France, 21000
Centre Leon Berard Recruiting
Lyon, France, 69008
Centre Rene Gauducheau Not yet recruiting
Saint Herblain, France, 44805
Institut Claudius Regaud; Departement Oncologie Medicale Recruiting
Toulouse, France, 31059
Institut Gustave Roussy; Sitep Not yet recruiting
VILLEJUIF Cedex, France, 94805
Italy
Fondazione IRCCS Istituto Nazionale dei Tumori;S.S. Trattamento MedicoTumori dellaTesta e delCollo Recruiting
Milano, Lombardia, Italy, 20133
Istituto Europeo di Oncologia; Svil. Nuovi Farmaci per Terapie Innovative Recruiting
Milano, Lombardia, Italy, 20141
Azienda Socio Sanitaria Territoriale Niguarda (Ospedale Niguarda Ca' Granda); Oncologico -Onc.Falck Recruiting
Milano, Lombardia, Italy, 20162
Ospedale Policlinico S. Matteo; Phase I Clinical Trial Unit and Experimental Therapy Recruiting
Pavia, Lombardia, Italy, 27100
Netherlands
Antoni Van Leeuwenhoek Ziekenhuis; Gastro-Enterologie Recruiting
Amsterdam, Netherlands, 1066 CX
Erasmus MC Recruiting
Rotterdam, Netherlands, 3015 GD
Spain
Clinica Universitaria de Navarra Active, not recruiting
Pamplona, Navarra, Spain, 31008
Hospital del Mar; Servicio de Oncologia Withdrawn
Barcelona, Spain, 08003
Hospital Univ Vall d'Hebron; Servicio de Oncologia Completed
Barcelona, Spain, 08035
Hospital Universitario 12 de Octubre; Servicio de Oncologia Withdrawn
Madrid, Spain, 28041
Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia Withdrawn
Valencia, Spain, 46010
United Kingdom
Leicester Royal Infirmary Recruiting
Leicester, United Kingdom, LE1 5WW
Barts Health NHS Trust - St Bartholomew's Hospital Recruiting
London, United Kingdom, EC1A 7BE
Guys and St Thomas NHS Foundation Trust, Guys Hospital Not yet recruiting
London, United Kingdom, SE1 9RT
Christie Hospital Recruiting
Manchester, United Kingdom, M20 3BG
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02627274     History of Changes
Other Study ID Numbers: BP29842
2015-002251-97 ( EudraCT Number )
First Posted: December 10, 2015    Key Record Dates
Last Update Posted: February 28, 2019
Last Verified: February 2019

Additional relevant MeSH terms:
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Head and Neck Neoplasms
Neoplasms by Site
Neoplasms
Trastuzumab
Cetuximab
Antineoplastic Agents, Immunological
Antineoplastic Agents