geavanceerde en/of gemetastaseerde solide tumoren cancer solid tumors
Conditions
Interventions
Eligible patients will be treated with RO5458640, and will follow the study
specific schedule as stated in table 12, 13 en14 (page 58 to 63 of the study
protocol).
Sponsors
Roche Nederland B.V.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1) Histologically or cytologically confirmed malignant solid tumors that are refractory or resistant to available therapies, or for which current therapy is not considered to provide benefit.;2) Patients must have measurable and/or evaluable disease;3) Tumor expression of the Fn14 receptor;4) Age >= 18 years;5) Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1;6) Estimated life expectancy of >= 12 weeks;7) Adequate bone marrow function, defined as ANC >=1.5 x 109/L, platelets > 100 x 109/L, and hemoglobin >=9.0 g/dL (5.6 mmol/L);8) Adequate liver function, defined as total bilirubin <1.5 x ULN, AST and ALT =60 mL/min [1.00mL/s/m2] (according to Cockroft-Gault formula, Appendix 5) ;10) Women of childbearing potential and women less than 2 years after menopause must have a negative pregnancy test result within 72 hours prior to receipt of study treatments.;11) Patients must be willing to use effective methods of contraception throughout study participation and for at least 90 days after the last dose of study medication. Female patients must be postmenopausal, surgically sterile, or agree to use physical barrier method of contraception. Oral or injectable agents must not be the sole method of contraception. Male patients must be surgically sterile or agree to use barrier method of contraception. ;12) Patients (or legal representative) must be willing and able to provide written informed consent.;13) Patients must be able and willing to comply with protocol requirements as determined by the study investigator. This includes study requirements for clinic visits, safety assessments, and consent for paired tumor biopsies as defined in Section 2.2 of the study protocol.
Exclusion criteria
Exclusion criteria: 1) Treatment with any investigational agent within 21 days prior to first dose of study treatment ;2) Prior chemotherapy, radiotherapy, or hormonal therapy for cancer within 3 weeks of first study treatment ;3) Receipt of antibody therapy or other immunotherapy currently or less than 21 days prior to study treatments, including interferons a or β, IL-2, etanercept, infliximab, adalimumab, golimumab, certolizumag pegol, cyclosporine, tacrolimus, and alefacept;4) Current immunosuppressive therapy, including those prescribed for organ transplantation and rheumatologic disease ;5) Corticosteroid therapy except for physiologic replacement dosages;6) Patients who have not recovered (> grade 1 NCI CTCAE severity) from prior adverse events related to any cancer therapy. An exception is made for alopecia. ;7) Pregnant or breast feeding women;8) Surgical procedure or clinically significant trauma within three weeks of study treatments. ;9) Known hypersensitivity to any component of RO5458640 or patients with previous severe hypersensitivity reactions to monoclonal antibody therapy.;10) History of active seizure disorder (event <= 2 months prior to study initiation or seizures not controlled with medication).;11)History of CNS or leptomeningeal metastases, except clinically stable disease characterized by ALL of the following: a) surgical resection or radiotherapy completed >= 3 months prior to first study drug, b) no corticosteroid requirements for >= 4 weeks prior to first study drug, c) stable CNS disease assessed by CT or MRI within 4 weeks of study drug, d) stable neurologic exam (no new focal or global abnormalities) for at least 4 weeks prior to first study drug. To confirm eligibility, a discussion between the Investigator and Sponsor is required for patients with CNS tumor. ;12) Serious cardiovascular illness, including but not limited to a) CVA or MI within 6 months of study initiation, b) CHF >= NYHA Class 2, unstable angina, symptomatic or otherwise uncontrolled arrhythmia requiring medication (does not include stable, lone atrial fibrillation), QTcF > 480 msecs (Fredericia correction method will be the primary evaluation parameter throughout the study), or uncontrolled hypertension;13) Active infection;14) Other uncontrolled, concurrent disease, including diabetes mellitus, pulmonary (clinically significant hypoxia requiring chronic, supplemental oxygen therapy), or altered mental status or psychiatric illness that would limit compliance with study requirements;15) A physical exam or laboratory finding that contra-indicates the use of investigational therapy or otherwise places the patient at excessively high risk for treatment, as determined by the study investigator. A discussion between the Investigator and Sponsor regarding eligibility is encouraged for such cases.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To characterize the safety, maximum tolerated dose, dose limiting toxicities, and recommended phase II dose (RP2D) for RO5458640 given intravenously on 3 administration schedules in patients with locally advanced or metastatic solid tumors. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary objectives: 1. To characterize RO5458640 pharmacokinetic profile (PK) on two administration schedules. 2. To assess response predictive markers of RO5458640 therapy: • Plasma TWEAK • Fn14 receptor expression from archival tissue and/or pre-study biopsy • Additional tumor characteristics which may be assessed for correlation with RO5458640 response or resistance include Fn14 mutations, Fn14 gene amplification, and constitutive NF*B pathway activation. 3. To describe anti-tumor activity according to RECIST 1.1 4. To evaluate antigenicity in response to RO5458640 treatment (Human anti-human antibody [HAHA] profile) 5. To characterize pharmacodynamic (PD) profiles in peripheral blood and tumor tissue samples in response to treatment with RO5458640. Functional imaging will also be assessed via [18F] - FDG PET/CT Assessments in peripheral blood may include baseline and posttreatment blood sampling for: • Target modulation: TWEAK ligand (ELISA) • Downregulation of NF*B transcription products: Cytokines IL-8 and CCL-2 • Investigation of pro-apoptotic MOA: Cleaved cytokeratin 18 and nucleosomal DNA • Other soluble markers related to TWEAK:Fn14 signaling, including but not limited to IL-6, IL-7 and MMP-9 PD Assessments in Tumor Tissue: Collection of pre and post treatment paired tumor biopsies are required for all patients. Assessments may include, but are not limited to the following: • Target modulation: Fn14 expression • Investigation of pro-apoptotic MOA: cPARP, TUNEL, cleaved caspace 3, cleaved cytokeratin 18 • Antiproliferative effects: pERK and Ki67 • Pathway modulation: TRAF1 (proximal signaling marker) • Additional markers related to TWEAK:Fn14 signaling may be considered, including but not limited to: CSF2, BIRC3, MMP9, CD68, pAKT , CD31 and gross vessel morphology (anti-angiogenic effects) Please see Tables 8, 9 , 10 and 11 in the study protocol for details related to schedule of tumor biopsies. Imaging: Uptake and reten | — |
Countries
Netherlands
Outcome results
None listed