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)

NCT02627274 | Completed Phase 1

• 2 other identifiers: BP298422015-002251-97
• Study Type: interventional
• Target: 134
• Locations: 9 countries
• Sites: 26

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).

Conditions

Solid Tumor; Breast Cancer; Cancer of Head and Neck

Outcome Measures

Primary Outcomes (8)

• Percentage of Participants With Dose-Limiting Toxicities (DLTs)

  Day 1 up to Day 21

• Maximum Tolerated Dose (MTD) of RO6874281

  Day 1 up to Day 21

• Optimal Biological Dose (OBD) of RO6874281

  Day 1 up to Day 21

• Recommended Dose for Further Development of RO6874281

  Day 1 up to Day 21

• Systemic Clearance (CL) of RO6874281

  Day 1 up to 24 months

• Volume of Distribution at Steady State (Vss) of RO6874281

  Day 1 up to 24 months

• Area Under the Concentration-Time Curve (AUC) of RO6874281

  Day 1 up to 24 months

• Maximum Observed Serum Concentration (Cmax) of RO6874281

  Day 1 up to 24 months

Secondary Outcomes (14)

• Number of T Cells in the Peripheral Blood

  Day 1 up to 24 months

• Number of Natural Killer (NK) Cells in the Peripheral Blood

  Day 1 up to 24 months

• Density of Cluster of Differentiation (CD)8+ Cells in Tumor Samples

  Day 1 up to 24 months

• Density of CD3-/Perforin+ Cells in Tumor Samples

  Day 1 up to 24 months

• Density of CD20 Cells in Tumor Samples

  Day 1 up to 24 months

Study Arms (3)

Part A: RO6874281 Monotherapy

EXPERIMENTAL

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

Part B: RO6874281 in Combination with Trastuzumab

EXPERIMENTAL

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.

Drug: RO6874281; Drug: Trastuzumab

Part C: RO6874281 in Combination with Cetuximab

EXPERIMENTAL

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: The MTD for RO6874281 was determined to be 10mg and therefore patients in the extension will be treated with 10mg RO6874281. Cetuximab and R06874281 will be administered weekly during induction phase (cycle 1 and cycle 2). Both IMPs will be administered Q2W starting in cycle 3.

Drug: RO6874281; Drug: Cetuximab

Interventions

RO6874281 DRUG

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

Also known as: simlukafusp alfa

Part A: RO6874281 Monotherapy; Part B: RO6874281 in Combination with Trastuzumab; Part C: RO6874281 in Combination with Cetuximab

Trastuzumab DRUG

Trastuzumab will be administered as per the schedule specified under arm description.

Also known as: Herceptin

Part B: RO6874281 in Combination with Trastuzumab

Cetuximab DRUG

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

Part C: RO6874281 in Combination with Cetuximab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (26)

University of Arizona Cancer Center

Tucson, Arizona, 85719, United States

Location

UCSD - Moores Cancer Center

La Jolla, California, 92037, United States

Location

Banner MD Anderson Cancer Center

Greeley, Colorado, 85234, United States

Location

Washington University; Division of Oncology

St Louis, Missouri, 63110, United States

Location

The Ohio State University

Columbus, Ohio, 43210, United States

Location

UZ Antwerpen

Edegem, 2650, Belgium

Location

Juravinski Cancer Clinic; Department of Oncology

Hamilton, Ontario, L8V 5C2, Canada

Location

Princess Margaret Cancer Center

Toronto, Ontario, M5G 1Z5, Canada

Location

Rigshospitalet; Onkologisk Klinik

København Ø, 2100, Denmark

Location

Institut Bergonie; Oncologie

Bordeaux, 33076, France

Location

Centre Georges Francois Leclerc

Dijon, 21000, France

Location

Centre Leon Berard

Lyon, 69008, France

Location

Institut Claudius Regaud; Departement Oncologie Medicale

Toulouse, 31059, France

Location

Institut Gustave Roussy; Sitep

Villejuif, 94805, France

Location

IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica

Meldola, Emilia-Romagna, 47014, Italy

Location

Fondazione IRCCS Istituto Nazionale dei Tumori;S.S. Trattamento MedicoTumori dellaTesta e delCollo

Milan, Lombardy, 20133, Italy

Location

Istituto Europeo di Oncologia; Svil. Nuovi Farmaci per Terapie Innovative

Milan, Lombardy, 20141, Italy

Location

Azienda Socio Sanitaria Territoriale Niguarda (Ospedale Niguarda Ca' Granda); Oncologico -Onc.Falck

Milan, Lombardy, 20162, Italy

Location

Ospedale Policlinico S. Matteo; Phase I Clinical Trial Unit and Experimental Therapy

Pavia, Lombardy, 27100, Italy

Location

Antoni Van Leeuwenhoek Ziekenhuis; Gastro-Enterologie

Amsterdam, 1066 CX, Netherlands

Location

Erasmus MC

Rotterdam, 3015 GD, Netherlands

Location

Clinica Universitaria de Navarra

Pamplona, Navarre, 31008, Spain

Location

Hospital Univ Vall d'Hebron; Servicio de Oncologia

Barcelona, 08035, Spain

Location

Leicester Royal Infirmary

Leicester, LE1 5WW, United Kingdom

Location

Guys and St Thomas NHS Foundation Trust, Guys Hospital

London, SE1 9RT, United Kingdom

Location

Christie Hospital

Manchester, M20 3BG, United Kingdom

Location

Related Publications (1)

• Hansen AR, Gomez-Roca CA, Robbrecht DGJ, Verlingue L, Italiano A, Bauman JE, Steeghs N, Prenen H, Fayette J, Spicer J, Niu J, Habigt C, Schneider M, Evers S, Sleiman N, Dejardin D, Ardeshir C, Schmid D, Boetsch C, Charo J, Kraxner A, Teichgraber V, Keshelava N, Bonomi MR. Phase Ib Study of the Immunocytokine Simlukafusp Alfa (FAP-IL2v) in Combination with Cetuximab in Patients with Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2024 Dec 16;30(24):5540-5547. doi: 10.1158/1078-0432.CCR-24-1562.

  PMID: 39422604 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Head and Neck Neoplasms

Interventions

Trastuzumab; Cetuximab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 26, 2015
• First Posted: December 10, 2015
• Study Start: December 7, 2015
• Primary Completion: November 10, 2022
• Study Completion: November 10, 2022
• Last Updated: November 22, 2022

Record last verified: 2022-11

Locations

NL (2); DK (1); FR (5); GB (3); CA (2); IT (5); ES (2); US (5); BE (1)