solide tumoren ( part A), Borstkanker (part B), (plaveiselcarcinoom hoofd/hals (partC) Cancer solid tumors
Conditions
Interventions
RO6874281 is considered an investigational medicinal product and will be
administered as an
IV infusion. The starting dose regimen of RO6874281 as a single agent will be 5
mg,
administered QW. Diffe
Sponsors
Roche Nederland B.V.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Age > 18 years - Radiologically measurable and clinically evaluable disease - Life expectancy of 12 weeks - Confirmed at least one tumor lesion with location accessible to safely biopsy per clinical judgment of the treating physician and the participant*s consented willingness to undergo baseline and on-treatment tumor biopsies for PD biomarker analysis - Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 - Patients with unilateral pleural effusion (other than non-small cell lung cancer [NSCLC] indication) should fulfill Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification 0-1 level and New York Health Association (NYHA) classification class 1 criteria for pulmonary and cardiac functions - Adequate cardiovascular, hematological, liver and renal function - All acute toxic effects of any prior radiotherapy, chemotherapy, or surgical procedure must have resolved to Grade 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 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% per year, during the treatment period and for at least 4 months after the last dose of study drug for RO6874281, and for at least 7 months after the last dose of trastuzumab. For cetuximab, please refer to local prescribing information for cetuximab - 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 drug or study treatment; - Patients with Gilbert*s syndrome will be eligible for the study; - 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 effective standard therapy that would confer clinical benefit to the patient exists - For Part B exclusively (RO6874281 in combination with trastuzumab), patients with metastatic or recurrent or locally advanced HER2-positive breast cancer, as defined by the College of American Pathologist 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 LVEF of >
Exclusion criteria
Exclusion criteria: Absence of rapid disease progression or threat to vital organs or critical anatomical sites (e.g., respiratory failure due to tumor compression, spinal cord compression) requiring urgent alternative medical intervention. * Symptomatic or untreated CNS metastases. * History of treated asymptomatic CNS metastases with any of the following criteria: o Metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm) o History of intracranial hemorrhage or spinal cord hemorrhage o Lacking radiographic demonstration of improvement upon the completion of CNS-directed therapy and evidence of interim progression between the completion of CNS-directed therapy and the baseline radiographic study o Ongoing requirement for dexamethasone as therapy for CNS disease; anticonvulsants at a stable dosage are allowed o Stereotactic radiation or whole-brain radiation within 28 days before study treatment administration o Last CNS radiographic study < 4 weeks since completion of radiotherapy and < 2 weeks since discontinuation of corticosteroids o CNS metastases treated by neurosurgical resection or brain biopsy performed within 28 days before study treatment administration - Patients 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 - Patients (all indications) with confirmed bilateral pleural effusion and NSCLC patients with confirmed uni-or bilateral pleural effusion by X-ray are not eligible - Significant cardiovascular/cerebrovascular vascular disease within 6 months prior to Day 1 of study drug administration - Active or uncontrolled infections - Known HIV, HBV, or hepatitis C (HCV) virus infection - Positive serology for hepatitis B (only for Parts B and C) - Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization within 4 weeks prior to the start of drug administration - 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 - Radiotherapy within the last 4 weeks before start of study drug treatment, with the exception of limited field palliative radiotherapy - History of progressive multifocal leukoencephalopathy - 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 trastuzum
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| SAFETY OUTCOME MEASURES The safety outcome measures for this study are as follows: * Incidence of DLTs * Incidence and severity of adverse events and IRRs * Incidence of laboratory abnormalities (hematology testing, coagulation, serum chemistries, urinalysis) * Incidence of anti-antibodies (ADAs) * Physical examination findings, particularly body weight * Triplicate 12-lead ECGs * Chest X-ray (or from computed tomography [CT] scan, if scheduled instead) *GOLD level classification: forced expiratory volume and forced vital capacity for the patients with pleural effusion at baseline (X-ray) that fulfill the eligibility criteria * Vital signs * TTE or MUGA scan EFFICACY OUTCOME MEASURES The efficacy/activity outcome measures for this study are as follows: * ORR * SD * DCR, defined as RR + SD * PFS, defined as the time from randomization to the first occurrence of disease progression or death from any cause *OS, if data are mature | — |
Secondary
| Measure | Time frame |
|---|---|
| For the pharmacokinetic and pharmacodynamic outcome measures, see page 117 en 1118 in the study protocol EXPLORATORY OUTCOME MEASURES The exploratory outcome measures for this study include but are not limited to the following: * The density and localization of immune cells will be determined in freshly obtained biopsy in order to describe the immune infiltration prior to treatment. When possible, comparisons between primary tumor and metastasis will be performed. * The density and activation status of immune cell subsets in the tumor will be assessed in biopsies taken before and during treatment. * Possible associations of genetic determinants of autoimmunity (e.g., KIR-HLA mismatch) with PD response and clinical response will be investigated. * The baseline values and kinetics of soluble markers of immune cell activation (such as sCD25) and tumor markers (such as soluble FAP [sFAP]) will be explored. Additional markers may be measured in case a strong scientific rationale for these analyses develops. * Assessment of TGK may be explored by comparing on-treatment and post treatment scans with at least two pretreatment scans not older than 12 weeks prior to Cycle 1 Day 1, if available. The two pretreatment scans consist of a pre-study scan and the study baseline scan. | — |
Countries
Netherlands
Outcome results
None listed