Ofatumumab is a novel Immunoglobulin 1ĸ ( IgG1ĸ) lytic monoclonal antibody (mAb) that specifically binds to the human Cluster of Differentiation 20 (CD20) antigen of which expression is restricted to B lymphocytes from the pre-B cell stage to the plasmacytoid immunoblast stage only. A recent trial with an anti-CD20 mAb (rituximab) demonstrated that targeting B-cells reduces the number of gadolinium-enhancing (GdE) T1 lesions and the relapse rate in relapsing-remitting multiple sclerosis (RRMS). Ofatumumab has been shown to be both well tolerated and efficacious in several indications, including a small, placebo-controlled trial in RRMS using an intravenous (IV) formulation.
This double-blind, placebo-controlled, parallel-group study will investigate the safety and efficacy of a subcutaneous formulation of ofatumumab in the treatment of subjects with RRMS. The primary objective of the study is to investigate the efficacy as assessed by magnetic resonance imaging. Other objectives will include evaluation of tolerability/safety, dose-response relationship, pharmacokinetics, pharmacodynamics, exposure-response, as well as other clinical endpoints.
The cumulative number of new GdE T1 lesion at Week 12 were analyzed from screening based on magnetic resonance imaging (MRI) brain scans at Weeks 4, 8, and 12. The outcome measure was analyzed using an Emax model adjusting for the presence/absence of GdE lesions on the Screening MRI and assuming the number of new lesions followed a negative binomial distribution. Dose was fitted as a continuous variable. The number of scans contributing to the cumulative number of lesions was fitted as an offset. Estimates of the rate of cumulative number of new GdE lesions per scan at Week 12 were determined from the model. The all evaluable scans (AES) dataset was used which included all evaluable on-treatment MRI scans for each participant analysed.
The cumulative number of new GdE T1 lesion at Week 24 were analyzed from screen based on MRI brain scans at Weeks 4, 8, 12, 16, 20 and 24. Anticipating an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative number of lesions was fitted as an offset. Estimates of the rate of cumulative number of new GdE T1 lesions per scan at Week 24 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each participant analyzed.
Change From Baseline in Brain Volume at Week 24 and Week 48 [ Time Frame: Baseline (Week 0), Week 24 and Week 48 ]
Brain volume is a measure of brain size determined by a MRI scan. Baseline is defined as the par. last available assessment prior to initiation of the IP (i.e. Screening). Change from Baseline was calculated by subtracting the Baseline value from the post-Baseline value.
The cumulative number of persistent GdE T1 lesions at Week 12 were analyzed from screen based on MRI scans at Weeks 4, 8, and 12. The AES dataset was used which included all evaluable on-treatment MRI scans for each par. analyzed.
The cumulative number of all (new plus persistent) GdE T1 lesion at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8 and 12. Anticipating an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative number of lesions was fitted as an offset. Estimates of the rate of cumulative number of all (new plus persistent) GdE T1 lesions per scan at Week 12 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each par. analyzed.
Lesion volume is a measure of lesion size determined by a MRI brain scan. The cumulative volume of new GdE T1 lesions at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8 and 12. Anticipating an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative volume of lesions was fitted as an offset. Estimates of the rate of cumulative volume of new GdE T1 lesions per scan at Week 12 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each par. analyzed.
Total Volume of All (New and Persistent) GdE Brain Lesions on T1-weighted MRI at Week 12 [ Time Frame: Week 12 ]
Lesion volume is a measure of lesion size determined by a MRI brain scan. The cumulative volume of all (new and persistent) GdE T1 lesions at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8 and 12. The endpoint was analyzed using a generalized linear model assuming an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative volume of lesions was fitted as an offset. Estimates of the rate of cumulative volume of all (new and persistent) GdE T1 lesions per scan at Week 12 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each par. analyzed.
The cumulative number of new and newly enlarging GdE T2 lesions (NET2L) at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8 and 12. The endpoint was analyzed using a generalized linear model assuming an underlying negative binomial distribution with a log-link function, adjusted for treatment and presence/absence of GdE lesions on the Screening MRI. Treatment group was fitted as a categorical variable. The number of scans contributing to the cumulative number of lesions was fitted as an offset. Estimates of the rate of cumulative number of NET2L per scan at Week 12 were determined from the model. The AES dataset was used which included all evaluable on-treatment MRI scans for each par. analyzed.
Lesion volume is a measure of lesion size determined by a MRI brain scan. T2 lesions, are indicative of brain myelin content.The cumulative volume of new and/or newly enlarging T2 lesions at Week 12 were analyzed from screen based on MRI brain scans at Weeks 4, 8, and 12. The AES dataset was used which included all evaluable on-treatment MRI scans for each par.
Cumulative Number of New T1 Hypointense Lesions at Week 24 and Week 48 [ Time Frame: Week 24 and Week 48 ]
The cumulative number of new T1 hypointense lesions at week 24 were analyzed from screen based on MRI brain scans at Weeks 4, 8, 12, 16, 20 and 24. The AES dataset was used which included all evaluable on-treatment MRI scans for each par.
Cumulative Volume of New T1 Hypointense Lesions at Week 24 and Week 48 [ Time Frame: Baseline, Week 24 and Week 48 ]
Lesion volume is a measure of lesion size determined by a MRI brain scan. Baseline is defined as the participant's last available assessment prior to initiation of IP. Change from Baseline was calculated by subtracting the Baseline value from the post-Baseline value. The AES dataset was used which included all evaluable on-treatment MRI scans for each par.
Definite diagnosis of MS according to the 2010 revisions of the McDonald diagnostic criteria for MS [Polman, 2011].
Subjects must have a relapsing-remitting course of disease with at least one of the following prior to screening:
At least one relapse in the previous 2 years, with a GdE brain lesion on an MRI scan in the past year.
Neurologically stable with no evidence of relapse for at least 30 days prior to start of Screening and during the Screening Phase (subjects who relapse during the screening Phase can be re-screened, once the relapse has resolved).
Of childbearing potential and NOT pregnant or nursing, has a negative serum pregnancy test at screening, and agrees to one of the following:
Complete abstinence from intercourse for the period from consent into the study until 6 months after the last dose of investigational product; or,
Consistent and correct use of one of the following acceptable methods of birth control for the period from consent into the study until 6 months after the last dose of investigational product:
A female is considered "Non-childbearing potential" if she is status-post hysterectomy, status-post surgical removal of both ovaries, has current, documented tubal ligation, or is postmenopausal and >2 years without menses. Female subjects who are post-menopausal <2 years must be confirmed menopausal by Follicle Stimulating Hormone (FSH) and estradiol levels.
A female is considered "childbearing potential" if she has functional ovaries, ducts, and uterus with no impairment that would cause sterility. This includes women with oligomenorrhea (even severe), and women who are perimenopausal or who have just begun to menstruate.
French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.
Unable to undergo MRI scans (e.g. due to pacemaker, severe claustrophobia, hypersensitivity to contrast media, or who lack adequate peripheral venous access).
Subjects whom experience a relapse during the Screening Phase. These subjects may be eligible for re-screening after consultation with GlaxoSmithKline (GSK).
History of clinically significant Central Nervous System (CNS) trauma (e.g. traumatic brain injury, cerebral contusion, spinal cord compression) or a history or presence of myelopathy due to spinal cord compression by disk or vertebral disease.
Any lymphocyte-depleting therapies, including, but not limited to: cladribine, anti-Cluster of Differentiation 4 (CD4), total body irradiation, or bone marrow transplantation
Any immunosuppressive agents, including, but not limited to: mitoxantrone, azathioprine, cyclosporine, cyclophosphamide, or tacrolimus
Significant concurrent, uncontrolled medical condition including, but not limited to, cardiac, renal, hepatic, hematological, gastrointestinal, endocrine, immunodeficiency syndrome, pulmonary, cerebral, psychiatric, or neurological disease which in the opinion of the investigator could affect the subject's safety, impair the subject's reliable participation in the trial, impair the evaluation of endpoints, or necessitate the use of medication not allowed by this protocol.
History of severe, clinically significant CNS trauma (e.g. cerebral contusion, spinal cord compression) or a history or presence of myelopathy due to spinal cord compression by disk or vertebral disease.
Positive polymerase chain reaction (PCR) screening for John Cunningham (JC) Virus as measured by plasma John Cunningham Virus (JCV) DNA.
Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded.
Subjects known or suspected of not being able to comply with a trial protocol (e.g. due to alcoholism, drug dependency or psychological disorder).
A documented history of attempted suicide over the 6 months prior to the screening visit, presents with suicidal ideation of type 4 or 5 on the C-Suicide Severity Rating Scale (SSRS) at the Screening visit, OR if in the investigator's judgment, the subject is at risk for a suicide attempt.
Use of an investigational drug or other experimental therapy for a condition other than MS within 4 weeks, 5 pharmacokinetic half lives or duration of biological effect (whichever is longer) prior to screening. Any prior use of an investigational drug or other experimental therapy for MS at any time should be discussed with the GSK Medical Monitor.
Current participation in any other interventional clinical trial. Participation in a non-interventional trial requires approval of the protocol by the GSK Medical Monitor
French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days
Olaparib and Ramucirumab in Treating Patients With Metastatic or Locally Recurrent Gastric or Gastroesophageal Junction Cancer That Cannot Be Removed by Surgery
This pilot phase I/II trial studies the side effects and best dose of olaparib when given together with ramucirumab and how well they work in treating patients with gastric or gastroesophageal junction cancer that has spread to other places in the body, has come back, or cannot be removed by surgery. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as ramucirumab, may interfere with the ability of tumor cells to grow and spread. Giving olaparib and ramucirumab may work better in treating patients with gastric or gastroesophageal junction cancer.
To determine the safe dose of olaparib with ramucirumab, but not to exceed olaparib dose of 300 mg twice daily (tablet formulation). (Phase I) II. To determine the efficacy of olaparib plus ramucirumab as measured by the objective response rates (ORR) stratified by BROCA-HR biomarker status. (Phase II).
III. To evaluate the association between findings from BROCA-HR panel and signature 3 results with response to therapy.
To create a PDX model to study deoxyribonucleic acid (DNA) repair in gastric tumors treated with PARP inhibitors (PARPi) from both pre-treatment biopsy and repeat biopsy after 16 weeks of treatment.
Patients receive olaparib orally (PO) twice daily (BID) on days 1-14 and ramucirumab intravenously (IV) over 60 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 4 weeks and then every 3-6 weeks thereafter.
The patient must have histologically confirmed, gastric carcinoma, including gastroesophageal junction (GEJ) adenocarcinoma (patients with adenocarcinoma of the distal esophagus are eligible if the primary tumor involves the GEJ)
The patient must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
The patient must have experienced disease progression during or within 4 months after the last dose of chemotherapy for metastatic disease, during or within 6 months after the last dose of adjuvant chemotherapy, or have been intolerant of previous chemotherapy
The patient must have experienced disease progression or intolerance as outlined above after treatment with 1 or more prior chemotherapies
All previous treatments are acceptable as long as they did not contain bevacizumab,ramucirumab or PARP inhibitors
Elevation in tumor markers without radiographic evidence of disease progression is not satisfactory for progression on previous treatment
Hemoglobin ≥ 10 g/dL with no blood transfusions (packed red blood cells and platelet transfusions) in the past 28 days, within 28 days prior to administration of study treatment
Absolute neutrophil count (ANC) >= 1.5 109/L, within 28 days prior to administration of study treatment
No features suggestive of MDS/AML on peripheral blood smear or bone marrow biopsy, if clinically indicated, within 28 days prior to administration of study treatment
Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN), within 28 days prior to administration of study treatment
Calculated serum creatinine clearance >= 60 mL/min/1.73 m2, within 28 days prior to administration of study treatment
Proteinuria with urinary protein is =< 1+ on dipstick or routine urinalysis, or a 24-hour urine collection for protein < 1000 mg of protein in 24 hours, within 28 days prior to administration of study treatment
Coagulation parameters (international normalized ratio [INR], activated partial thromboplastin time [aPTT]) =< 1.25 x institutional limits, except where a lupus anti-coagulant has been confirmed or the patient is on warfarin; patients on full dose anticoagulation must be on a stable dose for at least 14 days. If receiving warfarin,the patient must have an INR =< 3.0 without any evidence of active bleeding within 14 days prior to first dose of study treatment or a pathologic condition that carries a high risk of bleeding (tumor involvement with major blood vessels or varicies), within 28 days prior to administration of study treatment
Postmenopausal or evidence of non-childbearing status for women of childbearing potential a negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1; postmenopausal is defined as:
Women of child-bearing potential and men must agree to use adequate contraception including hormonal, barrier, or abstinence; contraception must be started prior to study enrollment; female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; both men and women treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study participation, and for 3 months after completion of olaparib and ramucirumab administration; male patients and their partners, who are sexually active and of childbearing potential, must agree to the use of two highly effective forms of contraception in combination, throughout the period of taking study treatment and for 3 months after last dose of study drug(s) to prevent pregnancy in a partner
The patient must be willing to undergo repeat biopsy at week 16 (for the first 20 patients in the phase 2 part of the study)
Patients must be able to tolerate oral medications by mouth, and not have a gastrointestinal illness that would preclude absorption of olaparib
Adequately controlled blood pressure (BP) < 140 mmHg (systolic) and < 90 mmHg(diastolic) taken in the clinic setting by a medical professional within 2 weeks prior to starting study; patients with hypertension may be managed with up to a maximum of 3 antihypertensive medications; a cardiologist or blood pressure specialist must evaluate patients who are on 3 antihypertensive medications within 4 weeks of enrollment
Patients who have the following risk factors are considered to be at increased risk for cardiac toxicity and must have documented left ventricular ejection fraction(LVEF) by echocardiogram greater than institution's lower limit of normal (or 55% if threshold for normal not otherwise specified by institutional guidelines) obtained within 3 months
History of myocardial infarction within 12 months (patients with history of myocardial infarction within 6 months are excluded)
Patients with untreated brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events;a scan to confirm the absence of brain metastases is not required; the patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment; patients with spinal cord compression are also excluded unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
Patients who have not recovered from adverse events due to prior anti-cancer therapy(i.e., have residual toxicities > Common Terminology Criteria for Adverse Events(CTCAE) grade 1 or baseline, with the exception of alopecia)
The patient has experienced any grade 3-4 gastrointestinal bleeding within 3 months prior to randomization
The patient has experienced any arterial thrombotic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to enrollment
The patient has an ongoing or active infection, symptomatic congestive heart failure,unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia,uncontrolled thrombotic or hemorrhagic disorder, or any other serious uncontrolled medical disorder in the opinion of the investigator
The patient has an ongoing or active psychiatric illness or social situation that would limited compliance with study requirements
Clinically significant peripheral vascular disease or vascular disease (abdominal aortic aneurysm > 5 cm) or aortic dissection; if known history of abdominal aortic aneurysm with >= 4 cm in diameter, all of the following must be met
The patient has uncontrolled or poorly controlled hypertension despite standard medical management as defined in this protocol
Major surgery within 28 days of starting study treatment and patients must have recovered from any effects of any major surgery
An open biopsy, non-healing wound, ulcer or significant traumatic injury within 28 days prior to starting treatment (percutaneous, endobronchial, and endoscopic biopsies are allowed)
The patient has received chemotherapy, radiotherapy (except for palliative reasons),immunotherapy, or targeted therapy for gastric cancer within 3 weeks of study treatment
The patient has received prior therapy with bevacizumab, ramucirumab or any PARP inhibitor, including olaparib
Patients must not have evidence of coagulopathy or bleeding diathesis; therapeutic anticoagulation for prior thromboembolic events is permitted; the clinical indication for therapeutic anticoagulation must be clearly documented prior to enrollment and must be discussed with the principal investigator (PI); patients on greater than or equal to 2 anti-thrombotic agents, including but not limited to anti-platelet agents(nonsteroidal anti-inflammatory drugs [NSAIDS]/aspirin, clopidogrel), heparin, low molecular weight heparin, warfarin and a direct thrombin inhibitor will be excluded
The patient has elective or planned major surgery to be performed during the course of the clinical trial
History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib and ramucirumab
Patients with a known history of hepatitis B (defined as hepatitis B surface antigen[HBsAg] reactive) or known active hepatitis C virus (defined as detectable hepatitis C virus [HCV] ribonucleic acid [RNA]) infection; Note: no testing for hepatitis B and hepatitis C is required unless mandated by local health authority
The patient has a concurrent active malignancy other than treated non-melanoma skin cancers or in situ neoplasm; a patient with a prior history of malignancy is eligible,provided that they have been free of disease for >= 5 years
Patients may not have had a prior allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
Patients may not have features suggestive of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if clinically indicated
Patients may not have current signs and/or symptoms of bowel obstruction within 1 month prior to starting study drugs, except if it was a temporary incident (improved within < 24 hours [hr] with medical management)
Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4/5 are ineligible; the required washout period prior to starting treatment is 2 weeks for CYP3A inhibitors, 3 weeks for CYP3A inducers, and 5 weeks for enzalutamide; dihydropyridine calcium-channel blockers are permitted for management of hypertension
Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable
Current use of natural herb products or other complementary alternative medications;if used previously, patients must have at least 1-week washout and must stop using them while participating in this study
N° 728 of 802 Autocall Plus - Income Plan in Italy | Probability of 42.62% to outperform BTP learn more
This is a 2 year product paying in Euro issued by BNP Paribas. It is Digital Certificate linked to the performance of Deutsche Bank AG from 4/3/2017 to the last observation date 4/3/2019 and will be monitored at semiannual periods. The product will pay 3 additional 5% coupon(s) if the underlying is at or above the 70% of its initial level. At maturity, it will repay the initial investment plus a coupon of 5% so long as the worst performing underlying is at or above 70%. If the European protection barrier of 70% has not been breached, the nominal value will be paid, otherwise the product will repay the initial investment less any negative worst performing underlying measured over the term of the product