Histologically confirmed advanced and metastatic clear cell and papillary renal cell carcinoma MedDRA version: 19.1 Level: LLT Classification code 10038416 Term: Renal clear cell carcinoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 19.1 Level: PT Classification code 10038414 Term: Renal cell carcinoma stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version
Conditions
Interventions
Product Name: MEDI4736
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: MEDI4736
Current Sponsor code: MEDI4736
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equ
Sponsors
Queen Mary University of London
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: -Written informed consent prior to performing any protocol-related procedures, including study specific screening procedures -Age = 18 years at the time of study entry -Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 -Life expectancy =12 weeks -Histologically confirmed advanced (not amenable to curative surgery or radiation therapy) or metastatic (stage IV) renal cell cancer with a component of either clear cell cancer or papillary cancer. Patients with a component of both must be enrolled into the cohort with the predominant tumour type ---Clear cell renal cancer patients must have experienced progressive disease after exposure to VEGF targeted therapy ---Papillary cell renal cancer patients must be considered to be VEGF treatment naive or treatment refractory to be eligible -Evidence of measurable disease (i.e., =1 malignant tumour mass that can be accurately measured in at least 1 dimension = 20 mm with conventional computerized tomography CT Scan or Magnetic Resonance Imaging (MRI), or =10 mm with spiral CT scan using a 5 mm or smaller contiguous reconstruction algorithm). Bone lesions, ascites, peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions are not considered measurable -Adequate normal organ, marrow and coagulation function as defined by the following criteria: ---Haemoglobin = 9.0g/dL ---Absolute neutrophil count (ANC) =1.5 x 109/L (=1500/uL) without growth factor support ---Platelet count = 100 x 109 /L (=100,000/uL) ---Total serum bilirubin =1.5 x institutional upper limit of normal (ULN) (this will not apply to subjects with confirmed Gilbert’s syndrome [persistent or recurrent hyperbilirubinaemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology], who will be allowed only in consultation with their physician ---Serum transaminases (AST/ALT) =2.5 x the institutional ULN ---GFR =40mL/min as assessed using the standard methodology at the investigating sites (e.g. by Cockroft-Gault) ---International Normalisation Ration (INR) <1.5 x institutional ULN or activated partial thromboplastin time (aPTT) <1.5 x institutional ULN. This applies only to patients who do not receive therapeutic anti-coagulation -Representative formalin-fixed paraffin-embedded (FFPE) tumour block with an associated pathology report must be available for central testing and determined to be evaluable for tumour assessment of PD-L1 and Met. PD-L1 and Met related testing will be required prior to study only for the biomarker enrichment phase of the trial.(every effort should be made to obtain FFPE blocks however unstained fresh tissue slides and core needle biopsies will suffice) -Patients with known tumour thrombus or deep vein thrombosis (DVT) are eligible if stable on low molecular weight heparin (LMWH) for = 4 weeks -Negative serum or urine pregnancy test within 2 weeks prior to the first dose of IMP (for female patients of childbearing potential only). Non-childbearing potential is defined as: ---Post-menopausal defined as aged =50 years of age and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments OR ---Documented irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation OR ---<50 years of age who have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal tr
Exclusion criteria
Exclusion criteria: -Participation in another clinical study with an investigational product within 28 days prior to enrolment -Any previous treatment with an anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody, CD137 agonists, c-MET inhibitors or pathway-targeting agents, or CTLA-4. Patients with limited c-MET inhibitor exposure must be discussed with the CI -Receipt of the last dose of anti-cancer therapy within 2 weeks or five half-lives of the anti-cancer therapy prior to the first dose of study drug, or radical radiotherapy within 4 weeks prior to the first dose of study drug -Receiving strong inducers of CYP3A4, strong inhibitors of CYP3A4 or CYP1A2 or CYP3A4 substrates which have a narrow therapeutic range within 2 weeks before the first dose of study treatment (3 weeks for St John’s Wort) -Currently receiving treatment with therapeutic doses of warfarin sodium -Current or prior use of immunosuppressive medication within 21 days before the first dose of MEDI4736 or tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses -Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment -Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving MEDI4736 or anticipation that such a live, attenuated vaccine will be required during the study -Symptomatic or uncontrolled brain metastases requiring concurrent treatment, including surgery, radiation and/or corticosteroids -History of another primary malignancy other than RCC within 3 years prior to Cycle 1, Day 1 (see protocol for exceptions) -Mean resting QT interval corrected for heart rate >470ms calculated from triplicate ECGs -Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome) -Any unresolved toxicity of CTCAE grade >2 from previous anti-cancer therapy. Patients with irreversible toxicity that is not expected to be exacerbated by the IMP may be included -Any prior Grade =3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1 -Active or prior documented autoimmune disease within the past 2 years including myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. -Active or prior documented inflammatory bowel or history of gastrointestinal disorders which may interfere with the absorption of the study drug -History of primary immunodeficiency -History of allogeneic prior allogeneic stem cell or solid organ transplant -History of hypersensitivity to MEDI4736, tremelimumab, or any excipient or history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins -History of hypersensitivity to savolitinib and its excipients -Uncontrolled intercurrent illness including, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, or any fac
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: De-escalation phase (Ib) • Patients will be assessed for dose limiting toxicity throughout the treatment period, and dose de-escalation will occur when necessary. Expansion phase (IIa) • RECIST v1.1 measurements will be taken at baseline, week 4 and every 8 weeks until disease progression to assess overall response rate. Biomarker positive phase • RECIST v1.1 measurements will be taken at baseline, week 4 and every 8 weeks until disease progression to assess overall response rate.;Main Objective: De-escalation phase: To determine the recommended dose of MEDI4736 and savolitinib in combination by assessment of dose limiting toxicities. Expansion phase: To determine how well different combinations of MEDI4736, savolitinib and tremelimumab can reduce tumour sizes in patients with papillary and clear cell renal cell carcinoma. Biomarker phase: To determine how well different combinations of MEDI4736, savolitinib and tremelimumab can reduce tumour sizes in patients with clear cell renal cell carcinoma that express particular biomarkers.;Secondary Objective: De-escalation phase: - Assess the safety and tolerability of MEDI4736 and savolitinib in this patient population by collecting information about adverse events. - Investigate the pharmacokinetics (what the body does to drugs after administration) of the 2 drugs. Expansion phase: - Assess the effectiveness of combinations of MEDI4736, savolitinib and tremelimumab in this patient population by measuring progression-free survival, response rate,duration of response, and overall survival. - Assess the safety and tolerability of combinations of MEDI4736, savolitinib and tremelimumab in this patient population by collecting information about adverse events. Biomarker phase: - Assess the effectiveness of combinations of MEDI4736, savolitinib and tremelimumab in this patient population by measuring progression-free survival, duration of response, and overall survival. - Asses | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): De-escalation phase (Ib) • Measurement of pharmacokinetic (PK) parameter values for both savolitinib and MEDI4736. Expansion phase (IIa) • Progression free survival (PFS), defined as the time from study entry to disease progression or relapse (using RECIST v1.1) or death on study from any cause (defined as death within 30 days of the last study treatment), whichever occurs first. • Overall survival (OS), defined as the time from study entry to death from any cause. • Duration of response defined as the time from first documentation of CR or PR to disease progression (RECIST v1.1) or death from any cause, whichever occurs first. • Safety and tolerability as assessed by AEs (CTCAE v4.03) •Best response after 24 weeks of treatment .As assessed by RECIST v1.1 Biomarker phase: (Same as expansion phase above);Timepoint(s) of evaluation of this end point: De-escalation phase • PK parameter values will be measured on day 1 of cycle 1 and 2 (pre-dose, 1 hour and 3 hour post-dose sample). Expansion phase • PFS: For patients who have not died or experienced disease progression by the end of study, PFS will be censored on the last date the patient was known to be progression free • OS: All deaths will be included, whether they occur on study or following treatment discontinuation. For patients who have not died, OS will be censored at the date of last contact • Duration of response: RECIST v1.1 measurements taken at baseline, week 4 and every 8 weeks until disease progression • AEs will be collected every 4 weeks, at disease progression and after IMP discontinuation Biomarker phase: (Same as expansion phase above) | — |
Countries
Spain
Contacts
Public ContactSally Burtles
Queen Mary University of London
Outcome results
None listed